2000.0 ee 0.001 1.0 /kinetics[0]/MAPK[0]/MAPK_p_p[0]; /kinetics[0]/PKA[0]/PKA_active[0]; /kinetics[0]/CaMKII[0]/tot_CaM_CaMKII[0]; /kinetics[0]/CaMKII[0]/tot_autonomous_CaMKII[0]; /kinetics[0]/PKC[0]/PKC_active[0]; /kinetics[0]/MAPK[0]/Raf_p_GTP_Ras[0]; /kinetics[0]/MAPK[0]/craf_1_p[0]; /kinetics[0]/Ca[0]/Ca[0]; /kinetics[0]/CaM[0]/CaM_Ca4[0]; /kinetics[0]/PLCbeta[0]/DAG[0]; /kinetics[0]/PLCbeta[0]/IP3[0]; /kinetics[0]/PLA2[0]/Arachidonic_Acid[0]; /kinetics[0]/Ras[0]/GTP_Ras[0] CubeMesh False 0.0 0.0 red 0 0.0 0.0 14.7058823529 0.0 cyan 0 0.0 0.0 29.4117647059 0.0 orange 0 0.0 0.0 44.1176470588 0.0 pink 0 0.0 0.0 58.8235294118 0.0 yellow 0 0.0 0.0 73.5294117647 0.0 pink 0 0.0 0.0 88.2352941176 0.0 cyan 0 0.0 0.0 102.941176471 0.0 white 0 0.0 0.0 CoInit was .0624 117.647058824 0.0 white 0 0.0 0.0 7.35294117647 144.578313253 white 0 0.0 0.0 Marquez et al J. Immun 149,2560(92) est 1e6/cell for chromaffin cells We will use 1 uM as our initial concen 22.0588235294 144.578313253 white 0 0.0 0.0 66.1764705882 144.578313253 red 0 0.0 0.0 -1.0 135.0 white black 0.0 0.0 -1.0 125.0 white black 0.0 0.0 -1.0 116.0 white black 0.0 0.0 -1.0 106.0 white black 0.0 0.0 -1.0 96.0 white black 0.0 0.0 -1.0 87.0 white black 0.0 0.0 Calculated cytosolic was 20 nm from Wijkander and Sundler However, Leslie and Channon use about 400 nM. Need to confirm, but this is the value I use here. Another recalc of W_andS gives 1uM 147.058823529 0.0 yellow 1 0.0 0.0 161.764705882 0.0 yellow 1 0.0 0.0 -1.0 29.0 white black 0.0 0.0 176.470588235 0.0 cyan 1 0.0 0.0 -1.0 29.0 white black 0.0 0.0 191.176470588 0.0 cyan 1 0.0 0.0 -1.0 29.0 white black 0.0 0.0 205.882352941 0.0 pink 1 0.0 0.0 -1.0 29.0 white black 0.0 0.0 arachodonylphosphatidylcholine is the favoured substrate from Wijkander and Sundler, JBC 202 pp 873-880, 1991. Their assay used 30 uM substrate, which is what the kinetics in this model are based on. For the later model we should locate a more realistic value for APC. 220.588235294 0.0 yellow 1 0.0 0.0 Phosphorylated form of PLA2. Still need to hook it up using kinases. PKA: Wightman et al JBC 257 pp6650 1982 PKC: Many refs, eg Gronich et al JBC 263 pp 16645, 1988 but see Lin etal MAPK: Lin et al, Cell 72 pp 269, 1993. Show 3x with MAPK but not PKC alone Do not know if there is a Ca requirement for active phosphorylated state. 235.294117647 0.0 orange 1 0.0 0.0 -1.0 29.0 white black 0.0 0.0 250.0 0.0 orange 1 0.0 0.0 154.411764706 144.578313253 darkgreen 1 0.0 0.0 Total PLC = 0.8 uM see Ryu et al JBC 262 (26) pp 12511 1987 294.117647059 0.0 cyan 2 0.0 0.0 308.823529412 0.0 green 2 0.0 0.0 323.529411765 0.0 cyan 2 0.0 0.0 -1.0 29.0 white black 0.0 0.0 This should really be labelled PLC-G*GTP-Ca. This is the activated form of the enzyme. Mahama and Linderman assume that the IP3 precursors are not rate-limiting, but I will include those for completeness as they may be needed later. 338.235294118 0.0 cyan 2 0.0 0.0 -1.0 29.0 white black 0.0 0.0 352.941176471 0.0 cyan 2 0.0 0.0 Phosphatidylcholine is the main (around 55%) metabolic product of DAG, follwed by PE (around 25%). Ref is Welsh and Cabot, JCB35:231-245(1987) 367.647058824 0.0 green 2 0.0 0.0 323.529411765 144.578313253 green 2 0.0 0.0 Peak IP3 is perhaps 15 uM, basal _lessthan_= 0.2 uM. 338.235294118 144.578313253 pink 2 0.0 0.0 382.352941176 0.0 green 2 0.0 0.0 I am implementing this as acting only on the Rec-Gq complex, based on a more complete model PLC_Gq48.g which showed that the binding to the rec alone contributed only a small amount. 441.176470588 0.0 seagreen 3 0.0 0.0 455.882352941 0.0 seagreen 3 0.0 0.0 588.235294118 0.0 orange 4 0.0 0.0 -1.0 29.0 white black 0.0 0.0 -1.0 38.0 white black 0.0 0.0 -1.0 48.0 white black 0.0 0.0 -1.0 58.0 white black 0.0 0.0 -1.0 67.0 white black 0.0 0.0 -1.0 77.0 white black 0.0 0.0 Couldn't find any ref to the actual conc of craf-1 but I should try Strom et al Oncogene 5 pp 345 In line with the other kinases in the cascade, I estimate the conc to be 0.2 uM. To init we use 0.15, which is close to equil 602.941176471 0.0 pink 4 0.0 0.0 617.647058824 0.0 pink 4 0.0 0.0 -1.0 29.0 white black 0.0 0.0 -1.0 38.0 white black 0.0 0.0 Conc is from Seger et al JBC 267:20 pp14373 (1992) mwt is 45/46 Kd We assume that phosphorylation on both ser and thr is needed for activiation. See Kyriakis et al Nature 358 417 1992 Init conc of total is 0.18 632.352941176 0.0 pink 4 0.0 0.0 conc is from Sanghera et al JBC 265 pp 52 (1990) A second calculation gives 3.1 uM, from same paper. They est MAPK is 1e-4x total protein, and protein is 15% of cell wt, so MAPK is 1.5e-5g/ml = 0.36uM. which is closer to our first estimate. Lets use this. 647.058823529 0.0 pink 4 0.0 0.0 Negative feedback by MAPK* by hyperphosphorylating craf-1* gives rise to this pool. Ueki et al JBC 269(22):15756-15761, 1994 661.764705882 0.0 hotpink 4 0.0 0.0 Haystead et al FEBS Lett. 306(1) pp 17-22 show that phosphorylation is strictly sequential, first tyr185 then thr183. 676.470588235 0.0 orange 4 0.0 0.0 MAPKK phosphorylates MAPK on both the tyr and thr residues, first tyr then thr. Refs: Seger et al JBC267:20 pp 14373 1992 The MAPKK itself is phosphorylated on ser as well as thr residues. Let us assume that the ser goes first, and that the sequential phosphorylation is needed. See Kyriakis et al Nature 358 417-421 1992 691.176470588 0.0 pink 4 0.0 0.0 -1.0 29.0 white black 0.0 0.0 -1.0 38.0 white black 0.0 0.0 Intermediately phophorylated, assumed inactive, form of MAPKK 705.882352941 0.0 pink 4 0.0 0.0 595.588235294 144.578313253 red 4 0.0 0.0 -1.0 135.0 white black 0.0 0.0 -1.0 125.0 white black 0.0 0.0 610.294117647 144.578313253 27 4 0.0 0.0 Guanine nucleotide exchange factor. This activates raf by exchanging bound GDP with GTP. I have left the GDP/GTP out of this reaction, it would be trivial to put them in. See Boguski _and McCormick. Possible candidate molecules: RasGRF, smgGDS, Vav (in dispute). rasGRF: Kcat= 1.2/min Km = 680 nM smgGDS: Kcat: 0.37 /min, Km = 220 nM. vav: Turnover up over baseline by 10X, 735.294117647 0.0 hotpink 5 0.0 0.0 -1.0 29.0 white black 0.0 0.0 Assume that SoS is present only at 50 nM. Revised to 100 nM to get equil to experimentally known levels. 750.0 0.0 hotpink 5 0.0 0.0 -1.0 29.0 white black 0.0 0.0 phosphorylated and thereby activated form of GEF. See, e.g. Orita et al JBC 268:34 25542-25546 1993, Gulbins et al. It is not clear whether there is major specificity for tyr or ser/thr. 764.705882353 0.0 hotpink 5 0.0 0.0 -1.0 29.0 white black 0.0 0.0 Only a very small fraction (7% unstim, 15% stim) of ras is GTP-bound. Gibbs et al JBC 265(33) 20437 779.411764706 0.0 orange 5 0.0 0.0 GDP bound form. See Rosen et al Neuron 12 1207-1221 June 1994. the activation loop is based on Boguski and McCormick Nature 366 643-654 93 Assume Ras is present at about the same level as craf-1, 0.2 uM. Hallberg et al JBC 269:6 3913-3916 1994 estimate upto 5-10% of cellular Raf is assoc with Ras. Given that only 5-10% of Ras is GTP-bound, we need similar amounts of Ras as Raf. 794.117647059 0.0 pink 5 0.0 0.0 808.823529412 0.0 red 5 0.0 0.0 GTPase-activating proteins. See Boguski and McCormick. Turn off Ras by helping to hydrolyze bound GTP. This one is probably NF1, ie., Neurofibromin as it is inhibited by AA and lipids, and expressed in neural cells. p120-GAP is also a possible candidate, but is less regulated. Both may exist at similar levels. See Eccleston et al JBC 268(36) pp27012-19 Level=.002 823.529411765 0.0 red 5 0.0 0.0 -1.0 29.0 white black 0.0 0.0 Phosphorylation-inactivated form of GEF. See Hordijk et al JBC 269:5 3534-3538 1994 and Buregering et al EMBO J 12:11 4211-4220 1993 838.235294118 0.0 hotpink 5 0.0 0.0 See Farnsworth et al Nature 376 524-527 1995 852.941176471 0.0 pink 5 0.0 0.0 -1.0 29.0 white black 0.0 0.0 Berkers et al JBC 266 say 22K hi aff recs. Sherrill and Kyte Biochemistry 35 use range 4-200 nM. These match, lets use them. 882.352941176 0.0 red 6 0.0 0.0 This is terribly simplified: there are many interesting intermediate stages, including dimerization and assoc with adapter molecules like Shc, that contribute to the activation of the EGFR. 897.058823529 0.0 red 6 0.0 0.0 -1.0 29.0 white black 0.0 0.0 -1.0 38.0 white black 0.0 0.0 911.764705882 0.0 red 6 0.0 0.0 926.470588235 0.0 red 6 0.0 0.0 0.0 192.771084337 brown 7 0.0 0.0 -1.0 222.0 white black 0.0 0.0 There are 2 isoforms: 52 KDa and 46 KDa (See Okada et al JBC 270:35 pp 20737 1995). They are acted up on by the EGFR in very similar ways, and apparently both bind Grb2 similarly, so we'll bundle them together here. Sasaoka et al JBC 269:51 pp 32621 1994 show immunoprecs where it looks like there is at least as much Shc as Grb2. So we'll tentatively say there is 1 uM of Shc. 14.7058823529 192.771084337 orange 7 0.0 0.0 29.4117647059 192.771084337 orange 7 0.0 0.0 44.1176470588 192.771084337 orange 7 0.0 0.0 There is probably a lot of it in the cell: it is also known as Ash (abundant src homology protein I think). Also Waters et al JBC 271:30 18224 1996 say that only a small fraction of cellular Grb is precipitated out when SoS is precipitated. As most of the Sos seems to be associated with Grb2, it would seem like there is a lot of the latter. Say 1 uM. I haven't been able to find a decent.... 58.8235294118 192.771084337 orange 7 0.0 0.0 73.5294117647 192.771084337 orange 7 0.0 0.0 88.2352941176 192.771084337 red 7 0.0 0.0 I have tried using low (0.02 uM) initial concs, but these give a very flat response to EGF stim although the overall activation of Ras is not too bad. I am reverting to 0.1 because we expect a sharp initial response, followed by a decline. Sep 17 1997: The transient activation curve looks better with [Sos] = 0.05. Apr 26 1998: Some error there, it is better where it was at 0.1 102.941176471 192.771084337 red 7 0.0 0.0 117.647058824 192.771084337 42 7 0.0 0.0 Amount from Homma et al JBC 263:14 6592-6598 1988 147.058823529 192.771084337 pink 8 0.0 0.0 161.764705882 192.771084337 pink 8 0.0 0.0 176.470588235 192.771084337 pink 8 0.0 0.0 191.176470588 192.771084337 pink 8 0.0 0.0 205.882352941 192.771084337 33 8 0.0 0.0 -1.0 222.0 white black 0.0 0.0 Huge conc of CaMKII. In PSD it is 20-40% of protein, so we assume it is around 2.5% of protein in spine as a whole. This level is so high it is unlikely to matter much if we are off a bit. This comes to about 70 uM. 294.117647059 192.771084337 palegreen 9 0.0 0.0 308.823529412 192.771084337 palegreen 9 0.0 0.0 From Hanson and Schulman, the thr286 is responsible for autonomous activation of CaMKII. 323.529411765 192.771084337 palegreen 9 0.0 0.0 From Hanson and Schulman, the CaMKII does a lot of autophosphorylation just after the CaM is released. This prevents further CaM binding and renders the enzyme quite independent of Ca. 338.235294118 192.771084337 cyan 9 0.0 0.0 I am not sure if we need to endow this one with a lot of enzs. It is likely to be a short-lived intermediate, since it will be phosphorylated further as soon as the CAM falls off. 352.941176471 192.771084337 red 9 0.0 0.0 This forms due to basal autophosphorylation, but I think it has to be considered as a pathway even if some CaM is floating around. In either case it will tend to block further binding of CaM, and will not display any enzyme activity. See Hanson and Schulman JBC 267:24 pp17216-17224 1992 367.647058824 192.771084337 palegreen 9 0.0 0.0 316.176470588 289.156626506 green 9 0.0 0.0 -1.0 318.0 white black 0.0 0.0 -1.0 328.0 white black 0.0 0.0 375.0 289.156626506 green 9 0.0 0.0 -1.0 318.0 white black 0.0 0.0 -1.0 328.0 white black 0.0 0.0 441.176470588 192.771084337 blue 10 0.0 0.0 There is a LOT of this in the cell: upto 1% of total protein mass. (Alberts et al) Say 25 uM. Meyer et al Science 256 1199-1202 1992 refer to studies saying it is comparable to CaMK levels. 455.882352941 192.771084337 pink 10 0.0 0.0 470.588235294 192.771084337 red 10 0.0 0.0 The phosph form does not bind CaM (Huang et al ABB 305:2 570-580 1993) 485.294117647 192.771084337 red 10 0.0 0.0 Also known as RC3 and p17 and BICKS. Conc in brain _greaterthan__greaterthan_ 2 uM from Martzen and Slemmon J neurosci 64 92-100 1995 but others say less without any #s. Conc in dend spines is much higher than overall, so it could be anywhere from 2 uM to 50. We will estimate 10 uM as a starting point. Gerendasy et al JBC 269:35 22420-22426 1994 have a skeleton model (no numbers) indicating CaM-Ca(n) binding .... 500.0 192.771084337 red 10 0.0 0.0 514.705882353 192.771084337 hotpink 10 0.0 0.0 544.117647059 192.771084337 darkblue 10 0.0 0.0 -1.0 222.0 white black 0.0 0.0 -1.0 231.0 white black 0.0 0.0 -1.0 241.0 white black 0.0 0.0 558.823529412 192.771084337 tan 10 0.0 0.0 -1.0 222.0 white black 0.0 0.0 This is the intermediate where the TR2 end (the high-affinity end) has bound the Ca but the TR1 end has not. 448.529411765 337.34939759 pink 10 0.0 0.0 This is the intermediate where the TR2 end (the high-affinity end) has bound the Ca but the TR1 end has not. 463.235294118 337.34939759 pink 10 0.0 0.0 Cohen et al Meth Enz 159 390-408 is main source of info conc = 1.8 uM 588.235294118 192.771084337 cyan 11 0.0 0.0 -1.0 222.0 white black 0.0 0.0 -1.0 231.0 white black 0.0 0.0 -1.0 241.0 white black 0.0 0.0 -1.0 250.0 white black 0.0 0.0 -1.0 260.0 white black 0.0 0.0 I1 is a 'mixed' inhibitor, but at high enz concs it looks like a non-compet inhibitor (Foulkes et al Eur J Biochem 132 309-313 9183). We treat it as non-compet, so it just turns the enz off without interacting with the binding site. Cohen et al ann rev bioch refer to results where conc is 1.5 to 1.8 uM. In order to get complete inhib of PP1, which is at 1.8 uM, we need _greaterthan_= 1.8 uM. 602.941176471 192.771084337 orange 11 0.0 0.0 Dephosph is mainly by PP2B 617.647058824 192.771084337 orange 11 0.0 0.0 632.352941176 192.771084337 brown 11 0.0 0.0 647.058823529 192.771084337 brown 11 0.0 0.0 We assume that the A and B subunits of PP2B are always bound under physiol conditions. Up to 1% of brain protein = 25 uM. I need to work out how it is distributed between cytosolic and particulate fractions. Tallant and Cheung '83 Biochem 22 3630-3635 have conc in many species, average for mammalian brain is around 1 uM. 735.294117647 192.771084337 tan 12 0.0 0.0 750.0 192.771084337 tan 12 0.0 0.0 764.705882353 192.771084337 blue 12 0.0 0.0 779.411764706 192.771084337 blue 12 0.0 0.0 794.117647059 192.771084337 blue 12 0.0 0.0 882.352941176 192.771084337 yellow 13 0.0 0.0 -1.0 222.0 white black 0.0 0.0 -1.0 231.0 white black 0.0 0.0 -1.0 241.0 white black 0.0 0.0 This is the R2C2 complex, consisting of 2 catalytic (C) subunits, and the R-dimer. See Taylor et al Ann Rev Biochem 1990 59:971-1005 for a review. The Doskeland and Ogreid review is better for numbers. Amount of PKA is about .5 uM. 897.058823529 192.771084337 white 13 0.0 0.0 CoInit was .0624 911.764705882 192.771084337 white 13 0.0 0.0 926.470588235 192.771084337 white 13 0.0 0.0 941.176470588 192.771084337 white 13 0.0 0.0 955.882352941 192.771084337 white 13 0.0 0.0 970.588235294 192.771084337 white 13 0.0 0.0 Starts at 0.15 for the test of fig 6 in Smith et al, but we aren't using that paper any more. 985.294117647 192.771084337 white 13 0.0 0.0 About 25% of PKA C subunit is dissociated in resting cells without having any noticable activity. Doskeland and Ogreid Int J biochem 13 pp1-19 suggest that this is because there is a corresponding amount of inhibitor protein. 1000.0 192.771084337 cyan 13 0.0 0.0 889.705882353 337.34939759 cyan 13 0.0 0.0 The conc of this has been a problem. Schaecter and Benowitz use 50 uM, but Shinomura et al have _lessthan_ 5. So I have altered the cAMP-dependent rates in the PKA model to reflect this. 0.0 385.542168675 green 14 0.0 0.0 ATP is present in all cells between 2 and 10 mM. See Lehninger. 14.7058823529 385.542168675 red 14 0.0 0.0 This version of cyclase is Calmodulin activated. Gs stims it but betagamma inhibits. 29.4117647059 385.542168675 orange 14 0.0 0.0 Starting conc at 20 nM. 44.1176470588 385.542168675 orange 14 0.0 0.0 This version is activated by Gs and by a betagamma and phosphorylation. 58.8235294118 385.542168675 yellow 14 0.0 0.0 73.5294117647 385.542168675 yellow 14 0.0 0.0 Starting at 0.015 uM. 88.2352941176 385.542168675 yellow 14 0.0 0.0 102.941176471 385.542168675 orange 14 0.0 0.0 117.647058824 385.542168675 green 14 0.0 0.0 The levels of the PDE are not known at this time. However, enough kinetic info and info about steady-state levels of cAMP etc are around to make it possible to estimate this. 7.35294117647 530.120481928 green 14 0.0 0.0 -1.0 520.0 white black 0.0 0.0 This form has about 2X activity as plain PDE. See Sette et al JBC 269:28 18271-18274 1994. 22.0588235294 530.120481928 green 14 0.0 0.0 -1.0 520.0 white black 0.0 0.0 CaM-Dependent PDE. Amount calculated from total rate in brain vs. specific rate. 36.7647058824 530.120481928 green 14 0.0 0.0 -1.0 520.0 white black 0.0 0.0 Activity up 6x following Ca-CaM binding. 51.4705882353 530.120481928 green 14 0.0 0.0 -1.0 520.0 white black 0.0 0.0 66.1764705882 530.120481928 pink 14 0.0 0.0 Varying the amount of (steady state) glu between .01 uM and up, the final amount of G*GTP complex does not change much. This means that the system should be reasonably robust wr to the amount of glu in the synaptic cleft. It would be nice to know how fast it is removed. 147.058823529 385.542168675 green 15 0.0 0.0 From M_andL, Total # of receptors/cell = 1900 Vol of cell = 1e-15 (10 um cube). Navogadro = 6.023e23 so conversion from n to conc in uM is n/vol*nA * 1e3 = 1.66e-6 However, for typical synaptic channels the density is likely to be very high at the synapse. Use an estimate of 0.1 uM for now. this gives a total of about 60K receptors/cell, which is in line with Fay et at. 161.764705882 385.542168675 green 15 0.0 0.0 This acts like an enzyme to activate the g proteins Assume cell has vol 1e-15 m^3 (10 uM cube), conversion factor to conc in uM is 6e5 176.470588235 385.542168675 green 15 0.0 0.0 Fraction of Rec-Gq is 44% of rec, from Fay et al. Since this is not the same receptor, this value is a bit doubtful. Still, we adjust the rate consts in Rec-bind-Gq to match. 191.176470588 385.542168675 green 15 0.0 0.0 205.882352941 385.542168675 orange 15 0.0 0.0 These exist in a nebulous sense in this model, basically only to balance the conservation equations. The details of their reassociation with G-GDP are not modeled Resting level =0.0094, stim level =.0236 from all42.g ish. 294.117647059 385.542168675 yellow 16 0.0 0.0 Activated G protein. Berstein et al indicate that about 20-40% of the total Gq alpha should bind GTP at steady stim. This sim gives more like 65%. 308.823529412 385.542168675 red 16 0.0 0.0 323.529411765 385.542168675 yellow 16 0.0 0.0 From M_andL, total Gprot = 1e5molecules/cell At equil, 92340 are here, 400 are in G*GTP, and another 600 are assoc with the PLC and 6475 are as G*GDP. This is OK. From Pang and Sternweis JBC 265:30 18707-12 1990 we get conc est 1.6 uM to 0.8 uM. A number of other factors are involved too. 338.235294118 385.542168675 yellow 16 0.0 0.0 352.941176471 385.542168675 red 16 0.0 0.0 MKP-1 dephosphoryates and inactivates MAPK in vivo: Sun et al Cell 75 487-493 1993. Levels of MKP-1 are regulated, and rise in 1 hour. Kinetics from Charles et al PNAS 90:5292-5296 1993. They refer to Charles et al Oncogene 7 187-190 who show that half-life of MKP1/3CH134 is 40 min. 80% deph of MAPK in 20 min Sep 17 1997: CoInit now 0.4x to 0.0032. See parm searches from jun96 on. 441.176470588 385.542168675 hotpink 17 0.0 0.0 -1.0 414.0 white black 0.0 0.0 -1.0 424.0 white black 0.0 0.0 Refs: Pato et al Biochem J 293:35-41(93); Takai_andMieskes Biochem J 275:233-239 k1=1.46e-4, k2=1000,k3=250. these use kcat values for calponin. Also, units of kcat may be in min! revert to Vmax base: k3=6, k2=25,k1=3.3e-6 or 6,6,1e-6 CoInit assumed 0.1 uM. See NOTES for MAPK_Ras50.g. CoInit now 0.08 Sep 17 1997: Raise CoInt 1.4x to 0.224, see parm searches from jun 96 on. 455.882352941 385.542168675 hotpink 17 0.0 0.0 -1.0 414.0 white black 0.0 0.0 -1.0 424.0 white black 0.0 0.0 -1.0 434.0 white black 0.0 0.0 -1.0 443.0 white black 0.0 0.0 -1.0 405.0 white black 0.0 0.0 470.588235294 385.542168675 red 17 0.0 0.0 -1.0 414.0 white black 0.0 0.0 -1.0 424.0 white black 0.0 0.0 -1.0 434.0 white black 0.0 0.0 -1.0 443.0 white black 0.0 0.0 -1.0 453.0 white black 0.0 0.0 -1.0 463.0 white black 0.0 0.0 -1.0 472.0 white black 0.0 0.0 -1.0 482.0 white black 0.0 0.0 -1.0 491.0 white black 0.0 0.0 -1.0 501.0 white black 0.0 0.0 -1.0 511.0 white black 0.0 0.0 -1.0 520.0 white black 0.0 0.0 -1.0 530.0 white black 0.0 0.0 588.235294118 385.542168675 red 18 0.0 0.0 This isn't explicitly present in the M_andL model, but is obviously needed. I assume its conc is fixed at 1uM for now, which is a bit high. PLA2 is stim 7x by PIP2 @ 0.5 uM (Leslie and Channon BBA 1045:261(1990) Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs, which comes to 50 nM. Ref is Majerus et al Cell 37 pp 701-703 1984 Lets use a lower level of 30 nM, same ref.... 735.294117647 385.542168675 green 19 0.0 0.0 779.411764706 385.542168675 43 19 0.0 0.0 794.117647059 385.542168675 37 19 0.0 0.0 -1.0 414.0 white black 0.0 0.0 808.823529412 385.542168675 brown 19 0.0 0.0 -1.0 414.0 white black 0.0 0.0 823.529411765 385.542168675 cyan 19 0.0 0.0 838.235294118 385.542168675 10 19 0.0 0.0 -1.0 414.0 white black 0.0 0.0 852.941176471 385.542168675 44 19 0.0 0.0 742.647058824 530.120481928 50 19 0.0 0.0 757.352941176 530.120481928 37 19 0.0 0.0 -1.0 520.0 white black 0.0 0.0 794.117647059 530.120481928 31 19 0.0 0.0 -1.0 520.0 white black 0.0 0.0 882.352941176 385.542168675 53 20 0.0 0.0 897.058823529 385.542168675 9 20 0.0 0.0 -1.0 414.0 white black 0.0 0.0 911.764705882 385.542168675 39 20 0.0 0.0 -1.0 414.0 white black 0.0 0.0 926.470588235 385.542168675 60 20 0.0 0.0 aaa 941.176470588 385.542168675 25 20 0.0 0.0 -1.0 414.0 white black 0.0 0.0 -1.0 424.0 white black 0.0 0.0 955.882352941 385.542168675 4 20 0.0 0.0 0.0 578.313253012 yellow 21 0.0 0.0 14.7058823529 578.313253012 3 21 0.0 0.0 29.4117647059 578.313253012 38 21 0.0 0.0 44.1176470588 578.313253012 45 21 0.0 0.0 58.8235294118 578.313253012 red 21 0.0 0.0 -1.0 607.0 white black 0.0 0.0 -1.0 617.0 white black 0.0 0.0 147.058823529 578.313253012 28 22 0.0 0.0 161.764705882 578.313253012 39 22 0.0 0.0 176.470588235 578.313253012 25 22 0.0 0.0 191.176470588 578.313253012 44 22 0.0 0.0 -1.0 607.0 white black 0.0 0.0 -1.0 617.0 white black 0.0 0.0 -1.0 626.0 white black 0.0 0.0 294.117647059 578.313253012 46 23 0.0 0.0 308.823529412 578.313253012 Pink 23 0.0 0.0 323.529411765 578.313253012 48 23 0.0 0.0 -1.0 607.0 white black 0.0 0.0 338.235294118 578.313253012 6 23 0.0 0.0 -1.0 607.0 white black 0.0 0.0 -1.0 617.0 white black 0.0 0.0 352.941176471 578.313253012 45 23 0.0 0.0 -1.0 607.0 white black 0.0 0.0 441.176470588 578.313253012 47 24 0.0 0.0 455.882352941 578.313253012 59 24 0.0 0.0 470.588235294 578.313253012 52 24 0.0 0.0 485.294117647 578.313253012 56 24 0.0 0.0 500.0 578.313253012 39 24 0.0 0.0 514.705882353 578.313253012 60 24 0.0 0.0 Q.R= Quaternary complex.Ribosome 588.235294118 578.313253012 blue 25 0.0 0.0 602.941176471 578.313253012 pink 25 0.0 0.0 Q= Quaternary complex 617.647058824 578.313253012 28 25 0.0 0.0 40S_complex consist of Quaternary complex, mRNA complex, 40S Ribosomes. 632.352941176 578.313253012 hotpink 25 0.0 0.0 735.294117647 578.313253012 cyan 26 0.0 0.0 750.0 578.313253012 brown 26 0.0 0.0 764.705882353 578.313253012 white 26 0.0 0.0 779.411764706 578.313253012 red 26 0.0 0.0 794.117647059 578.313253012 45 26 0.0 0.0 808.823529412 578.313253012 1 26 0.0 0.0 823.529411765 578.313253012 47 26 0.0 0.0 838.235294118 578.313253012 2 26 0.0 0.0 882.352941176 578.313253012 44 27 0.0 0.0 0.0 771.084337349 32 28 0.0 0.0 14.7058823529 771.084337349 58 28 0.0 0.0 -1.0 800.0 white black 0.0 0.0 29.4117647059 771.084337349 45 28 0.0 0.0 -1.0 800.0 white black 0.0 0.0 44.1176470588 771.084337349 57 28 0.0 0.0 147.058823529 771.084337349 42 29 0.0 0.0 161.764705882 771.084337349 cyan 29 0.0 0.0 176.470588235 771.084337349 pink 29 0.0 0.0 191.176470588 771.084337349 21 29 0.0 0.0 205.882352941 771.084337349 6 29 0.0 0.0 220.588235294 771.084337349 60 29 0.0 0.0 235.294117647 771.084337349 59 29 0.0 0.0 294.117647059 771.084337349 27 30 0.0 0.0 308.823529412 771.084337349 white 30 0.0 0.0 323.529411765 771.084337349 46 30 0.0 0.0 338.235294118 771.084337349 52 30 0.0 0.0 -1.0 800.0 white black 0.0 0.0 -1.0 810.0 white black 0.0 0.0 352.941176471 771.084337349 blue 30 0.0 0.0 It will contribute to mTOR independent translation. 367.647058824 771.084337349 53 30 0.0 0.0 -1.0 800.0 white black 0.0 0.0 -1.0 810.0 white black 0.0 0.0 Inactivated form of S6K 441.176470588 771.084337349 3 31 0.0 0.0 Activated form of S6 455.882352941 771.084337349 7 31 0.0 0.0 470.588235294 771.084337349 44 31 0.0 0.0 -1.0 800.0 white black 0.0 0.0 588.235294118 771.084337349 40 32 0.0 0.0 602.941176471 771.084337349 51 32 0.0 0.0 -1.0 800.0 white black 0.0 0.0 735.294117647 771.084337349 45 33 0.0 0.0 750.0 771.084337349 61 33 0.0 0.0 764.705882353 771.084337349 46 33 0.0 0.0 779.411764706 771.084337349 52 33 0.0 0.0 794.117647059 771.084337349 59 33 0.0 0.0 -1.0 800.0 white black 0.0 0.0 Bychkov et al., 2011. 150ng/mg *0.5mg/ml /65000g/mol = 1.155385nM (which is too low, therefore increasing the concentration arbitrarily by 1000 fold) 882.352941176 771.084337349 42 34 0.0 0.0 -1.0 800.0 white black 0.0 0.0 897.058823529 771.084337349 24 34 0.0 0.0 Bychkov et al., 2011. 30ng/mg *0.5mg/ml /40000g/mol = 0.375nM (which is too low, therefore increasing the concentration arbitrarily by 1000 fold) 911.764705882 771.084337349 19 34 0.0 0.0 926.470588235 771.084337349 0 34 0.0 0.0 941.176470588 771.084337349 53 34 0.0 0.0 955.882352941 771.084337349 61 34 0.0 0.0 970.588235294 771.084337349 39 34 0.0 0.0 985.294117647 771.084337349 50 34 0.0 0.0 $\mathrm{PKC\_DAG\_AA\_p\_466\_0\_}+\mathrm{PKC\_Ca\_memb\_p\_470\_0\_}+\mathrm{PKC\_Ca\_AA\_p\_468\_0\_}+\mathrm{PKC\_DAG\_memb\_p\_472\_0\_}+\mathrm{PKC\_basal\_p\_474\_0\_}+\mathrm{PKC\_AA\_p\_476\_0\_}$ $\mathrm{CaMKII\_CaM\_820\_0\_}+\mathrm{CaMKII\_thr286\_p\_CaM\_822\_0\_}$ $\mathrm{CaMKII\_thr286\_826\_0\_}+\mathrm{CaMKII\_p\_p\_p\_824\_0\_}$ $\mathrm{CaMCa4\_CaNAB\_941\_0\_}+\mathrm{CaMCa3\_CaNAB\_937\_0\_}+\mathrm{CaMCa2\_CaNAB\_939\_0\_}$ Need est of rate of assoc of Ca and PKC. Assume it is fast The original parameter-searched kf of 439.4 has been scaled by 1/6e8 to account for change of units to n. Kf now 8.16e-7, kb=.6085 Raised kf to 1e-6 to match Ca curve, kb to .5 7.35294117647 19.2771084337 white 0 kinetics_455_0_ * PKC_act_by_Ca_506_0__Kf * PKC_cytosolic_484_0_*Ca_1174_0_-kinetics_455_0_ * PKC_act_by_Ca_506_0__Kb * PKC_Ca_464_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_Ca\_506\_0\_\_Kf}\mathrm{PKC\_cytosolic\_484\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_Ca\_506\_0\_\_Kb}\mathrm{PKC\_Ca\_464\_0\_}$ Need est of rate. Assume it is fast Obtained from param search kf raised 10 X : see Shinomura et al PNAS 88 5149-5153 1991. kf changed from 3.865e-7 to 2.0e-7 in line with closer analysis of Shinomura data. 26 June 1996: Corrected DAG data: reduce kf 15x from 2e-7 to 1.333e-8 22.0588235294 19.2771084337 white 0 kinetics_455_0_ * PKC_act_by_DAG_508_0__Kf * PKC_Ca_464_0_*DAG_609_0_-kinetics_455_0_ * PKC_act_by_DAG_508_0__Kb * PKC_Ca_DAG_478_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_DAG\_508\_0\_\_Kf}\mathrm{PKC\_Ca\_464\_0\_}\mathrm{DAG\_609\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_DAG\_508\_0\_\_Kb}\mathrm{PKC\_Ca\_DAG\_478\_0\_}$ 36.7647058824 19.2771084337 white 0 kinetics_455_0_ * PKC_Ca_to_memb_510_0__Kf * PKC_Ca_464_0_-kinetics_455_0_ * PKC_Ca_to_memb_510_0__Kb * PKC_Ca_memb_p_470_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_Ca\_to\_memb\_510\_0\_\_Kf}\mathrm{PKC\_Ca\_464\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_Ca\_to\_memb\_510\_0\_\_Kb}\mathrm{PKC\_Ca\_memb\_p\_470\_0\_}$ Raise kb from .087 to 0.1 to match data from Shinomura et al. Lower kf from 1.155 to 1.0 to match data from Shinomura et al. 51.4705882353 19.2771084337 white 0 kinetics_455_0_ * PKC_DAG_to_memb_512_0__Kf * PKC_Ca_DAG_478_0_-kinetics_455_0_ * PKC_DAG_to_memb_512_0__Kb * PKC_DAG_memb_p_472_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_DAG\_to\_memb\_512\_0\_\_Kf}\mathrm{PKC\_Ca\_DAG\_478\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_DAG\_to\_memb\_512\_0\_\_Kb}\mathrm{PKC\_DAG\_memb\_p\_472\_0\_}$ Schaechter and Benowitz We have to increase Kf for conc scaling Changed kf to 2e-9 on Sept 19, 94. This gives better match. 66.1764705882 19.2771084337 white 0 kinetics_455_0_ * PKC_act_by_Ca_AA_514_0__Kf * PKC_Ca_464_0_*Arachidonic_Acid_573_0_-kinetics_455_0_ * PKC_act_by_Ca_AA_514_0__Kb * PKC_Ca_AA_p_468_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_Ca\_AA\_514\_0\_\_Kf}\mathrm{PKC\_Ca\_464\_0\_}\mathrm{Arachidonic\_Acid\_573\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_Ca\_AA\_514\_0\_\_Kb}\mathrm{PKC\_Ca\_AA\_p\_468\_0\_}$ Assume slowish too. Schaechter and Benowitz 80.8823529412 19.2771084337 white 0 kinetics_455_0_ * PKC_act_by_DAG_AA_516_0__Kf * PKC_DAG_AA_482_0_-kinetics_455_0_ * PKC_act_by_DAG_AA_516_0__Kb * PKC_DAG_AA_p_466_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_DAG\_AA\_516\_0\_\_Kf}\mathrm{PKC\_DAG\_AA\_482\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_DAG\_AA\_516\_0\_\_Kb}\mathrm{PKC\_DAG\_AA\_p\_466\_0\_}$ Initial basal levels were set by kf = 1, kb = 20. In model, though, the basal levels of PKC activity are higher. 95.5882352941 19.2771084337 white 0 kinetics_455_0_ * PKC_basal_act_518_0__Kf * PKC_cytosolic_484_0_-kinetics_455_0_ * PKC_basal_act_518_0__Kb * PKC_basal_p_474_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_basal\_act\_518\_0\_\_Kf}\mathrm{PKC\_cytosolic\_484\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_basal\_act\_518\_0\_\_Kb}\mathrm{PKC\_basal\_p\_474\_0\_}$ Raise kf from 1.667e-10 to 2e-10 to get better match to data. 110.294117647 19.2771084337 white 0 kinetics_455_0_ * PKC_act_by_AA_520_0__Kf * PKC_cytosolic_484_0_*Arachidonic_Acid_573_0_-kinetics_455_0_ * PKC_act_by_AA_520_0__Kb * PKC_AA_p_476_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_AA\_520\_0\_\_Kf}\mathrm{PKC\_cytosolic\_484\_0\_}\mathrm{Arachidonic\_Acid\_573\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_act\_by\_AA\_520\_0\_\_Kb}\mathrm{PKC\_AA\_p\_476\_0\_}$ kf raised 10 X based on Shinomura et al PNAS 88 5149-5153 1991 closer analysis of Shinomura et al: kf now 1e-8 (was 1.66e-8). Further tweak. To get sufficient AA synergy, increase kf to 1.5e-8 26 June 1996: Corrected DAG levels: reduce kf by 15x from 1.5e-8 to 1e-9 125.0 19.2771084337 white 0 kinetics_455_0_ * PKC_n_DAG_522_0__Kf * DAG_609_0_*PKC_cytosolic_484_0_-kinetics_455_0_ * PKC_n_DAG_522_0__Kb * PKC_DAG_480_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_n\_DAG\_522\_0\_\_Kf}\mathrm{DAG\_609\_0\_}\mathrm{PKC\_cytosolic\_484\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_n\_DAG\_522\_0\_\_Kb}\mathrm{PKC\_DAG\_480\_0\_}$ Reduced kf to 0.66X to match Shinomura et al data. Initial: kf = 3.3333e-9 New: 2e-9 Newer: 2e-8 kb was 0.2 now 2. 14.7058823529 125.301204819 white 0 kinetics_455_0_ * PKC_n_DAG_AA_524_0__Kf * PKC_DAG_480_0_*Arachidonic_Acid_573_0_-kinetics_455_0_ * PKC_n_DAG_AA_524_0__Kb * PKC_DAG_AA_482_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_n\_DAG\_AA\_524\_0\_\_Kf}\mathrm{PKC\_DAG\_480\_0\_}\mathrm{Arachidonic\_Acid\_573\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PKC\_n\_DAG\_AA\_524\_0\_\_Kb}\mathrm{PKC\_DAG\_AA\_482\_0\_}$ Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267. 154.411764706 19.2771084337 white 1 kinetics_455_0_ * PLA2_Ca_act_559_0__Kf * PLA2_cytosolic_528_0_*Ca_1174_0_-kinetics_455_0_ * PLA2_Ca_act_559_0__Kb * PLA2_Ca_p_530_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PLA2\_Ca\_act\_559\_0\_\_Kf}\mathrm{PLA2\_cytosolic\_528\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PLA2\_Ca\_act\_559\_0\_\_Kb}\mathrm{PLA2\_Ca\_p\_530\_0\_}$ 169.117647059 19.2771084337 white 1 kinetics_455_0_ * PIP2_PLA2_act_561_0__Kf * PLA2_cytosolic_528_0_*temp_PIP2_1178_0_-kinetics_455_0_ * PIP2_PLA2_act_561_0__Kb * PIP2_PLA2_p_535_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PIP2\_PLA2\_act\_561\_0\_\_Kf}\mathrm{PLA2\_cytosolic\_528\_0\_}\mathrm{temp\_PIP2\_1178\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PIP2\_PLA2\_act\_561\_0\_\_Kb}\mathrm{PIP2\_PLA2\_p\_535\_0\_}$ 183.823529412 19.2771084337 white 1 kinetics_455_0_ * PIP2_Ca_PLA2_act_563_0__Kf * PLA2_Ca_p_530_0_*temp_PIP2_1178_0_-kinetics_455_0_ * PIP2_Ca_PLA2_act_563_0__Kb * PIP2_Ca_PLA2_p_540_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PIP2\_Ca\_PLA2\_act\_563\_0\_\_Kf}\mathrm{PLA2\_Ca\_p\_530\_0\_}\mathrm{temp\_PIP2\_1178\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PIP2\_Ca\_PLA2\_act\_563\_0\_\_Kb}\mathrm{PIP2\_Ca\_PLA2\_p\_540\_0\_}$ 27 June 1996 Scaled kf down by 0.015 from 3.33e-7 to 5e-9 to fit with revised DAG estimates and use of mole-fraction to calculate eff on PLA2. 198.529411765 19.2771084337 white 1 kinetics_455_0_ * DAG_Ca_PLA2_act_565_0__Kf * DAG_609_0_*PLA2_Ca_p_530_0_-kinetics_455_0_ * DAG_Ca_PLA2_act_565_0__Kb * DAG_Ca_PLA2_p_545_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{DAG\_Ca\_PLA2\_act\_565\_0\_\_Kf}\mathrm{DAG\_609\_0\_}\mathrm{PLA2\_Ca\_p\_530\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{DAG\_Ca\_PLA2\_act\_565\_0\_\_Kb}\mathrm{DAG\_Ca\_PLA2\_p\_545\_0\_}$ I need to check if the AA degradation pathway really leads back to APC. Anyway, it is a convenient buffered pool to dump it back into. For the purposes of the full model we use a rate of degradation of 0.2/sec Raised decay to 0.4 : see PLA35.g notes for Feb17 213.235294118 19.2771084337 white 1 kinetics_455_0_ * Degrade_AA_567_0__Kf * Arachidonic_Acid_573_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Degrade\_AA\_567\_0\_\_Kf}\mathrm{Arachidonic\_Acid\_573\_0\_}$ To start off, same kinetics as the PLA2-Ca-act direct pathway. Oops ! Missed out the Ca input to this pathway first time round. Let's raise the forward rate about 3x to 5e-6. This will let us reduce the rather high rates we have used for the kenz on PLA2*-Ca. In fact, it may be that the rates are not that different, just that this pathway for getting the PLA2 to the memb is more efficien.... 227.941176471 19.2771084337 white 1 kinetics_455_0_ * PLA2_p_Ca_act_569_0__Kf * PLA2_p_557_0_*Ca_1174_0_-kinetics_455_0_ * PLA2_p_Ca_act_569_0__Kb * PLA2_p_Ca_552_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PLA2\_p\_Ca\_act\_569\_0\_\_Kf}\mathrm{PLA2\_p\_557\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PLA2\_p\_Ca\_act\_569\_0\_\_Kb}\mathrm{PLA2\_p\_Ca\_552\_0\_}$ 242.647058824 19.2771084337 white 1 kinetics_455_0_ * dephosphorylate_PLA2_p_571_0__Kf * PLA2_p_557_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosphorylate\_PLA2\_p\_571\_0\_\_Kf}\mathrm{PLA2\_p\_557\_0\_}$ Affinity for Ca = 1uM without AlF, 0.1 with: from Smrcka et al science 251 pp 804-807 1991 so [Ca].kf = kb so kb/kf = 1 * 6e5 = 1/1.66e-6 11 June 1996: Raised affinity to 5e-6 to maintain balance. See notes. 301.470588235 19.2771084337 white 2 kinetics_455_0_ * Act_PLC_Ca_593_0__Kf * PLC_577_0_*Ca_1174_0_-kinetics_455_0_ * Act_PLC_Ca_593_0__Kb * PLC_Ca_581_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Act\_PLC\_Ca\_593\_0\_\_Kf}\mathrm{PLC\_577\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Act\_PLC\_Ca\_593\_0\_\_Kb}\mathrm{PLC\_Ca\_581\_0\_}$ The enzyme is IP3 5-phosphomonesterase. about 45K. Actual products are Ins(1,4)P2, and cIns(1:2,4,5)P3. review in Majerus et al Science 234 1519-1526, 1986. Meyer and Stryer 1988 PNAS 85:5051-5055 est decay of IP3 at 1-3/sec 316.176470588 19.2771084337 white 2 kinetics_455_0_ * Degrade_IP3_595_0__Kf * IP3_611_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Degrade\_IP3\_595\_0\_\_Kf}\mathrm{IP3\_611\_0\_}$ These rates are the same as for degrading IP3, but I am sure that they could be improved. Lets double kf to 0.2, since the amount of DAG in the cell should be _lessthan_= 1uM. Need to double it again, for the same reason. kf now 0.5 27 June 1996 kf is now 0.02 to get 50 sec time course 30 Aug 1997: Raised kf to 0.11 to accomodate PLC_gamma 27 Mar 1998: kf now 0.15 for PLC_gamma 330.882352941 19.2771084337 white 2 kinetics_455_0_ * Degrade_DAG_597_0__Kf * DAG_609_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Degrade\_DAG\_597\_0\_\_Kf}\mathrm{DAG\_609\_0\_}$ Affinity for Gq is _greaterthan_ 20 nM (Smrcka et al Science251 804-807 1991) so [Gq].kf = kb so 40nM * 6e5 = kb/kf = 24e3 so kf = 4.2e-5, kb =1 345.588235294 19.2771084337 white 2 kinetics_455_0_ * Act_PLC_by_Gq_599_0__Kf * G_pGTP_1090_0_*PLC_Ca_581_0_-kinetics_455_0_ * Act_PLC_by_Gq_599_0__Kb * PLC_Ca_Gq_586_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Act\_PLC\_by\_Gq\_599\_0\_\_Kf}\mathrm{G\_pGTP\_1090\_0\_}\mathrm{PLC\_Ca\_581\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Act\_PLC\_by\_Gq\_599\_0\_\_Kb}\mathrm{PLC\_Ca\_Gq\_586\_0\_}$ This process is assumed to be directly caused by the inactivation of the G*GTP to G*GDP. Hence, kf = .013 /sec = 0.8/min, same as the rate for Inact-G. kb = 0 since this is irreversible. We may be interested in studying the role of PLC as a GAP. If so, the kf would be faster here than in Inact-G 360.294117647 19.2771084337 white 2 kinetics_455_0_ * Inact_PLC_Gq_601_0__Kf * PLC_Ca_Gq_586_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Inact\_PLC\_Gq\_601\_0\_\_Kf}\mathrm{PLC\_Ca\_Gq\_586\_0\_}$ this binding does not produce active PLC. This step was needed to implement the described (Smrcka et al) increase in affinity for Ca by PLC once Gq was bound. The kinetics are the same as the binding step for Ca-PLC to Gq. June 1996: Changed the kf to 4.2e-5 to 4.2e-6 to preserve balance around the reactions. 375.0 19.2771084337 white 2 kinetics_455_0_ * PLC_bind_Gq_603_0__Kf * PLC_577_0_*G_pGTP_1090_0_-kinetics_455_0_ * PLC_bind_Gq_603_0__Kb * PLC_Gq_591_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PLC\_bind\_Gq\_603\_0\_\_Kf}\mathrm{PLC\_577\_0\_}\mathrm{G\_pGTP\_1090\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PLC\_bind\_Gq\_603\_0\_\_Kb}\mathrm{PLC\_Gq\_591\_0\_}$ this step has a high affinity for Ca, from Smrcka et al. 0.1uM so kf /kb = 1/6e4 = 1.666e-5:1. See the Act-PLC-by-Gq reac. 11 Jun 1996: Raised kf to 5e-5 based on match to conc-eff curves from Smrcka et al. 389.705882353 19.2771084337 white 2 kinetics_455_0_ * PLC_Gq_bind_Ca_605_0__Kf * Ca_1174_0_*PLC_Gq_591_0_-kinetics_455_0_ * PLC_Gq_bind_Ca_605_0__Kb * PLC_Ca_Gq_586_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PLC\_Gq\_bind\_Ca\_605\_0\_\_Kf}\mathrm{Ca\_1174\_0\_}\mathrm{PLC\_Gq\_591\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PLC\_Gq\_bind\_Ca\_605\_0\_\_Kb}\mathrm{PLC\_Ca\_Gq\_586\_0\_}$ The rate consts give a total binding affinity of only 448.529411765 19.2771084337 white 3 kinetics_455_0_ * Antag_bind_Rec_Gq_621_0__Kf * Rec_Gq_1072_0_*mGluRAntag_617_0_-kinetics_455_0_ * Antag_bind_Rec_Gq_621_0__Kb * Blocked_Rec_Gq_619_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Antag\_bind\_Rec\_Gq\_621\_0\_\_Kf}\mathrm{Rec\_Gq\_1072\_0\_}\mathrm{mGluRAntag\_617\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Antag\_bind\_Rec\_Gq\_621\_0\_\_Kb}\mathrm{Blocked\_Rec\_Gq\_619\_0\_}$ 595.588235294 19.2771084337 white 4 kinetics_455_0_ * mGluR_barr2_Raf_scaffolding_683_0__Kf * Internal_mGluR_p_dot_barr2_1524_0_*craf_1_645_0_-kinetics_455_0_ * mGluR_barr2_Raf_scaffolding_683_0__Kb * craf_1_p_647_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{mGluR\_barr2\_Raf\_scaffolding\_683\_0\_\_Kf}\mathrm{Internal\_mGluR\_p\_dot\_barr2\_1524\_0\_}\mathrm{craf\_1\_645\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{mGluR\_barr2\_Raf\_scaffolding\_683\_0\_\_Kb}\mathrm{craf\_1\_p\_647\_0\_}$ Assume the binding is fast and limited only by the amount of Ras* available. So kf=kb/[craf-1] If kb is 1/sec, then kf = 1/0.2 uM = 1/(0.2 * 6e5) = 8.3e-6 Later: Raise it by 10 X to 4e-5 From Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. So we raise kb 4x to 4 This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414 (I don't.... 742.647058824 19.2771084337 white 5 kinetics_455_0_ * Ras_act_craf_720_0__Kf * GTP_Ras_702_0_*craf_1_p_647_0_-kinetics_455_0_ * Ras_act_craf_720_0__Kb * Raf_p_GTP_Ras_673_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ras\_act\_craf\_720\_0\_\_Kf}\mathrm{GTP\_Ras\_702\_0\_}\mathrm{craf\_1\_p\_647\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Ras\_act\_craf\_720\_0\_\_Kb}\mathrm{Raf\_p\_GTP\_Ras\_673\_0\_}$ SoS/GEF is present at 50 nM ie 3e4/cell. BetaGamma maxes out at 9e4. Assume we have 1/3 of the GEF active when the BetaGamma is 1.5e4. so 1e4 * kb = 2e4 * 1.5e4 * kf, so kf/kb = 3e-5. The rate of this equil should be reasonably fast, say 1/sec 757.352941176 19.2771084337 white 5 kinetics_455_0_ * bg_act_GEF_722_0__Kf * BetaGamma_1088_0_*inact_GEF_692_0_-kinetics_455_0_ * bg_act_GEF_722_0__Kb * GEF_Gprot_bg_687_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{bg\_act\_GEF\_722\_0\_\_Kf}\mathrm{BetaGamma\_1088\_0\_}\mathrm{inact\_GEF\_692\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{bg\_act\_GEF\_722\_0\_\_Kb}\mathrm{GEF\_Gprot\_bg\_687\_0\_}$ 772.058823529 19.2771084337 white 5 kinetics_455_0_ * dephosph_GEF_724_0__Kf * GEF_p_697_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_GEF\_724\_0\_\_Kf}\mathrm{GEF\_p\_697\_0\_}$ This is extremely slow (1e-4), but it is significant as so little GAP actually gets complexed with it that the total GTP turnover rises only by 2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and Eccleston et al JBC 268(36) 27012-27019 kf = 1e-4 786.764705882 19.2771084337 white 5 kinetics_455_0_ * Ras_intrinsic_GTPase_726_0__Kf * GTP_Ras_702_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ras\_intrinsic\_GTPase\_726\_0\_\_Kf}\mathrm{GTP\_Ras\_702\_0\_}$ Assume a reasonably good rate for dephosphorylating it, 1/sec 801.470588235 19.2771084337 white 5 kinetics_455_0_ * dephosph_GAP_728_0__Kf * GAP_p_706_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_GAP\_728\_0\_\_Kf}\mathrm{GAP\_p\_706\_0\_}$ We have no numbers for this. It is probably between the two extremes represented by the CaMKII phosph states, and I have used guesses based on this. kf=1e-4 kb=1 The reaction is based on Farnsworth et al Nature 376 524-527 1995 816.176470588 19.2771084337 white 5 kinetics_455_0_ * CaM_bind_GEF_730_0__Kf * inact_GEF_692_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaM_bind_GEF_730_0__Kb * CaM_GEF_715_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_GEF\_730\_0\_\_Kf}\mathrm{inact\_GEF\_692\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_GEF\_730\_0\_\_Kb}\mathrm{CaM\_GEF\_715\_0\_}$ 830.882352941 19.2771084337 white 5 kinetics_455_0_ * dephosph_inact_GEF_p_732_0__Kf * inact_GEF_p_713_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_inact\_GEF\_p\_732\_0\_\_Kf}\mathrm{inact\_GEF\_p\_713\_0\_}$ Affinity of EGFR for EGF is complex: depends on [EGFR]. We'll assume fixed [EGFR] and use exptal affinity ~20 nM (see Sherrill and Kyte Biochem 1996 35 5705-5718, Berkers et al JBC 266:2 922-927 1991, Sorokin et al JBC 269:13 9752-9759 1994). Tau =~2 min (Davis et al JBC 263:11 5373-5379 1988) or Berkers Kass = 6.2e5/M/sec, Kdiss=3.5e-4/sec. Sherrill and Kyte have Hill Coeff=1.7 889.705882353 19.2771084337 white 6 kinetics_455_0_ * act_EGFR_750_0__Kf * EGFR_736_0_*EGF_746_0_-kinetics_455_0_ * act_EGFR_750_0__Kb * L_dot_EGFR_738_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{act\_EGFR\_750\_0\_\_Kf}\mathrm{EGFR\_736\_0\_}\mathrm{EGF\_746\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{act\_EGFR\_750\_0\_\_Kb}\mathrm{L\_dot\_EGFR\_738\_0\_}$ See Helin and Beguinot JBC 266:13 1991 pg 8363-8368. In Fig 3 they have internalization tau about 10 min, equil at about 20% EGF available. So kf = 4x kb, and 1/(kf + kb) = 600 sec so kb = 1/3K = 3.3e-4, and kf = 1.33e-3. This doesn't take into account the unbound receptor, so we need to push the kf up a bit, to 0.002 904.411764706 19.2771084337 white 6 kinetics_455_0_ * Internalize_752_0__Kf * L_dot_EGFR_738_0_-kinetics_455_0_ * Internalize_752_0__Kb * Internal_L_dot_EGFR_748_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Internalize\_752\_0\_\_Kf}\mathrm{L\_dot\_EGFR\_738\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Internalize\_752\_0\_\_Kb}\mathrm{Internal\_L\_dot\_EGFR\_748\_0\_}$ Time course of decline of phosph is 20 min. Part of this is the turnoff time of the EGFR itself. Lets assume a tau of 10 min for this dephosph. It may be wildly off. 7.35294117647 212.048192771 white 7 kinetics_455_0_ * SHC_p_dephospho_777_0__Kf * SHC_p_763_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{SHC\_p\_dephospho\_777\_0\_\_Kf}\mathrm{SHC\_p\_763\_0\_}$ Sasaoka et al JBC 269:51 pp 32621 1994, table on pg 32623 indicates that this pathway accounts for about 50% of the GEF activation. (88% - 39%). Error is large, about 20%. Fig 1 is most useful in constraining rates. Chook et al JBC 271:48 pp 30472, 1996 say that the Kd is 0.2 uM for Shc binding to EGFR. The Kd for Grb direct binding is 0.7, so we'll ignore it. 22.0588235294 212.048192771 white 7 kinetics_455_0_ * SHC_bind_Sos_dot_Grb2_779_0__Kf * Sos_dot_Grb2_769_0_*SHC_p_763_0_-kinetics_455_0_ * SHC_bind_Sos_dot_Grb2_779_0__Kb * SHC_p_dot_Sos_dot_Grb2_756_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{SHC\_bind\_Sos\_dot\_Grb2\_779\_0\_\_Kf}\mathrm{Sos\_dot\_Grb2\_769\_0\_}\mathrm{SHC\_p\_763\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{SHC\_bind\_Sos\_dot\_Grb2\_779\_0\_\_Kb}\mathrm{SHC\_p\_dot\_Sos\_dot\_Grb2\_756\_0\_}$ Same rates as Grb2_bind_Sos: Porfiri and McCormick JBC 271:10 pp 5871 1996 show that the binding is not affected by the phosph. 36.7647058824 212.048192771 white 7 kinetics_455_0_ * Grb2_bind_Sos_p_781_0__Kf * Sos_p_771_0_*Grb2_767_0_-kinetics_455_0_ * Grb2_bind_Sos_p_781_0__Kb * Sos_p_dot_Grb2_765_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Grb2\_bind\_Sos\_p\_781\_0\_\_Kf}\mathrm{Sos\_p\_771\_0\_}\mathrm{Grb2\_767\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Grb2\_bind\_Sos\_p\_781\_0\_\_Kb}\mathrm{Sos\_p\_dot\_Grb2\_765\_0\_}$ The only clue I have to these rates is from the time courses of the EGF activation, which is around 1 to 5 min. The dephosph would be expected to be of the same order, perhaps a bit longer. Lets use 0.002 which is about 8 min. Sep 17: The transient activation curve matches better with kf = 0.001 51.4705882353 212.048192771 white 7 kinetics_455_0_ * dephosph_Sos_783_0__Kf * Sos_p_771_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_Sos\_783\_0\_\_Kf}\mathrm{Sos\_p\_771\_0\_}$ As there are 2 SH3 domains, this reaction could be 2nd order. I have a Kd of 22 uM from peptide binding (Lemmon et al JBC 269:50 pg 31653). However, Chook et al JBC 271:48 pg30472 say it is 0.4uM with purified proteins, so we believe them. They say it is 1:1 binding. 66.1764705882 212.048192771 white 7 kinetics_455_0_ * Grb2_bind_Sos_785_0__Kf * Sos_773_0_*Grb2_767_0_-kinetics_455_0_ * Grb2_bind_Sos_785_0__Kb * Sos_dot_Grb2_769_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Grb2\_bind\_Sos\_785\_0\_\_Kf}\mathrm{Sos\_773\_0\_}\mathrm{Grb2\_767\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Grb2\_bind\_Sos\_785\_0\_\_Kb}\mathrm{Sos\_dot\_Grb2\_769\_0\_}$ 80.8823529412 212.048192771 white 7 kinetics_455_0_ * Grb2_bind_SHC_787_0__Kf * SHC_p_763_0_*Grb2_767_0_-kinetics_455_0_ * Grb2_bind_SHC_787_0__Kb * SHC_p_Grb2_clx_775_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Grb2\_bind\_SHC\_787\_0\_\_Kf}\mathrm{SHC\_p\_763\_0\_}\mathrm{Grb2\_767\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Grb2\_bind\_SHC\_787\_0\_\_Kb}\mathrm{SHC\_p\_Grb2\_clx\_775\_0\_}$ Nice curves from Homma et al JBC 263:14 6592-6598 1988 Fig 5c. The activity falls above 10 uM, but that is too high to reach physiologically anyway, so we'll ignore the higher pts and match the lower ones only. Half-max at 1 uM. But Wahl et al JBC 267:15 10447-10456 1992 have half-max at 56 nM which is what I'll use. 154.411764706 212.048192771 white 8 kinetics_455_0_ * Ca_act_PLC_g_808_0__Kf * Ca_1174_0_*PLC_g_791_0_-kinetics_455_0_ * Ca_act_PLC_g_808_0__Kb * Ca_dot_PLC_g_795_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_act\_PLC\_g\_808\_0\_\_Kf}\mathrm{Ca\_1174\_0\_}\mathrm{PLC\_g\_791\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_act\_PLC\_g\_808\_0\_\_Kb}\mathrm{Ca\_dot\_PLC\_g\_795\_0\_}$ Again, we refer to Homma et al and Wahl et al, for preference using Wahl. Half-Max of the phosph form is at 316 nM. Use kb of 10 as this is likely to be pretty fast. Did some curve comparisons, and instead of 316 nM giving a kf of 5.27e-5, we will use 8e-5 for kf. 16 Sep 97. As we are now phosphorylating the Ca-bound form, equils have shifted. kf should now be 2e-5 to match the curves. 169.117647059 212.048192771 white 8 kinetics_455_0_ * Ca_act_PLC_g_p_810_0__Kf * PLC_g_p_793_0_*Ca_1174_0_-kinetics_455_0_ * Ca_act_PLC_g_p_810_0__Kb * Ca_dot_PLC_g_p_799_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_act\_PLC\_g\_p\_810\_0\_\_Kf}\mathrm{PLC\_g\_p\_793\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_act\_PLC\_g\_p\_810\_0\_\_Kb}\mathrm{Ca\_dot\_PLC\_g\_p\_799\_0\_}$ 183.823529412 212.048192771 white 8 kinetics_455_0_ * dephosph_PLC_g_812_0__Kf * Ca_dot_PLC_g_p_799_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_PLC\_g\_812\_0\_\_Kf}\mathrm{Ca\_dot\_PLC\_g\_p\_799\_0\_}$ 198.529411765 212.048192771 white 8 kinetics_455_0_ * PLC_g_p_dephospho_814_0__Kf * PLC_g_p_793_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PLC\_g\_p\_dephospho\_814\_0\_\_Kf}\mathrm{PLC\_g\_p\_793\_0\_}$ This is tricky. There is some cooperativity here arising from interactions between the subunits of the CAMKII holoenzyme. However, the stoichiometry is 1. Kb/Kf = 6e4 #/cell. Rate is fast (see Hanson et al Neuron 12 943-956 1994) so lets say kb = 10. This gives kf = 1.6667e-4 H_andS AnnRev Biochem 92 give tau for dissoc as 0.2 sec at low Ca, 0.4 at high. Low Ca = 100 nM = physiol. 301.470588235 212.048192771 white 9 kinetics_455_0_ * CaMKII_bind_CaM_846_0__Kf * CaMKII_818_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaMKII_bind_CaM_846_0__Kb * CaMKII_CaM_820_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaMKII\_bind\_CaM\_846\_0\_\_Kf}\mathrm{CaMKII\_818\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaMKII\_bind\_CaM\_846\_0\_\_Kb}\mathrm{CaMKII\_CaM\_820\_0\_}$ Affinity is up 1000X. Time to release is about 20 sec, so the kb is OK at 0.1 This makes Kf around 1.6666e-3 316.176470588 212.048192771 white 9 kinetics_455_0_ * CaMKII_thr286_bind_CaM_848_0__Kf * CaMKII_thr286_826_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaMKII_thr286_bind_CaM_848_0__Kb * CaMKII_thr286_p_CaM_822_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaMKII\_thr286\_bind\_CaM\_848\_0\_\_Kf}\mathrm{CaMKII\_thr286\_826\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaMKII\_thr286\_bind\_CaM\_848\_0\_\_Kb}\mathrm{CaMKII\_thr286\_p\_CaM\_822\_0\_}$ This reaction represents one of the big unknowns in CaMK-II biochemistry: what maintains the basal level of phosphorylation on thr 286 ? See Hanson and Schulman Ann Rev Biochem 1992 61:559-601, specially pg 580, for review. I have not been able to find any compelling mechanism in the literature, but fortunately the level of basal activity is well documented. 330.882352941 212.048192771 white 9 kinetics_455_0_ * basal_activity_850_0__Kf * CaMKII_818_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{basal\_activity\_850\_0\_\_Kf}\mathrm{CaMKII\_818\_0\_}$ Use K3 = 21.5 uM here from Stemmer and Klee table 3. kb/kf =21.5 * 6e5 so kf = 7.75e-7, kb = 10 477.941176471 212.048192771 white 10 kinetics_455_0_ * CaM_Ca3_bind_Ca_886_0__Kf * CaM_Ca3_864_0_*Ca_1174_0_-kinetics_455_0_ * CaM_Ca3_bind_Ca_886_0__Kb * CaM_Ca4_854_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca3\_bind\_Ca\_886\_0\_\_Kf}\mathrm{CaM\_Ca3\_864\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca3\_bind\_Ca\_886\_0\_\_Kb}\mathrm{CaM\_Ca4\_854\_0\_}$ Surprisingly, no direct info on rates from neurogranin at this time. These rates are based on GAP-43 binding studies. As GAP-43 and neurogranin share near identity in the CaM/PKC binding regions, and also similarity in phosph and dephosph rates, I am borrowing GAP-43 kinetic info. See Alexander et al JBC 262:13 6108-6113 1987 492.647058824 212.048192771 white 10 kinetics_455_0_ * neurogranin_bind_CaM_888_0__Kf * CaM_856_0_*neurogranin_862_0_-kinetics_455_0_ * neurogranin_bind_CaM_888_0__Kb * neurogranin_CaM_858_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{neurogranin\_bind\_CaM\_888\_0\_\_Kf}\mathrm{CaM\_856\_0\_}\mathrm{neurogranin\_862\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{neurogranin\_bind\_CaM\_888\_0\_\_Kb}\mathrm{neurogranin\_CaM\_858\_0\_}$ This is put in to keep the basal levels of neurogranin* experimentally reasonable. From various papers, specially Ramakers et al JBC 270:23 1995 13892-13898, it looks like the basal level of phosph is between 20 and 40%. I est around 25 % The kf of 0.005 gives around this level at basal PKC activity levels of 0.1 uM active PKC. 507.352941176 212.048192771 white 10 kinetics_455_0_ * dephosph_neurogranin_890_0__Kf * neurogranin_p_860_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_neurogranin\_890\_0\_\_Kf}\mathrm{neurogranin\_p\_860\_0\_}$ Lets use the fast rate consts here. Since the rates are so different, I am not sure whether the order is relevant. These correspond to the TR2C fragment. We use the Martin et al rates here, plus the Drabicowski binding consts. All are scaled by 3X to cell temp. kf = 2e-10 kb = 72 Stemmer _and Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11. If kb=72, kf = 2e-10 (Exactly the same !) 19 May 2006. Splitting the old CaM-TR2-bind-Ca reaction into two steps, each binding 1 Ca. This improves numerical stability and is conceptually better too. Overall rates are the same, so each kf and kb is the square root of the earlier ones. So kf = 1.125e-4, kb = 8.4853 522.058823529 212.048192771 white 10 kinetics_455_0_ * CaM_bind_Ca_892_0__Kf * CaM_856_0_*Ca_1174_0_-kinetics_455_0_ * CaM_bind_Ca_892_0__Kb * CaM_Ca_884_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_Ca\_892\_0\_\_Kf}\mathrm{CaM\_856\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_Ca\_892\_0\_\_Kb}\mathrm{CaM\_Ca\_884\_0\_}$ K3 = 21.5, K4 = 2.8. Assuming that the K4 step happens first, we get kb/kf = 2.8 uM = 1.68e6 so kf =6e-6 assuming kb = 10 536.764705882 212.048192771 white 10 kinetics_455_0_ * CaM_Ca2_bind_Ca_894_0__Kf * CaM_Ca2_882_0_*Ca_1174_0_-kinetics_455_0_ * CaM_Ca2_bind_Ca_894_0__Kb * CaM_Ca3_864_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca2\_bind\_Ca\_894\_0\_\_Kf}\mathrm{CaM\_Ca2\_882\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca2\_bind\_Ca\_894\_0\_\_Kb}\mathrm{CaM\_Ca3\_864\_0\_}$ Lets use the fast rate consts here. Since the rates are so different, I am not sure whether the order is relevant. These correspond to the TR2C fragment. We use the Martin et al rates here, plus the Drabicowski binding consts. All are scaled by 3X to cell temp. kf = 2e-10 kb = 72 Stemmer _and Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11. If kb=72, kf = 2e-10 (Exactly the same !) 19 May 2006. Splitting the old CaM-TR2-bind-Ca reaction into two steps, each binding 1 Ca. This improves numerical stability and is conceptually better too. Overall rates are the same, so each kf and kb is the square root of the earlier ones. So kf = 1.125e-4, kb = 8.4853 551.470588235 212.048192771 white 10 kinetics_455_0_ * CaM_Ca_bind_Ca_896_0__Kf * CaM_Ca_884_0_*Ca_1174_0_-kinetics_455_0_ * CaM_Ca_bind_Ca_896_0__Kb * CaM_Ca2_882_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca\_bind\_Ca\_896\_0\_\_Kf}\mathrm{CaM\_Ca\_884\_0\_}\mathrm{Ca\_1174\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca\_bind\_Ca\_896\_0\_\_Kb}\mathrm{CaM\_Ca2\_882\_0\_}$ 566.176470588 212.048192771 white 10 kinetics_455_0_ * CaMKIII_bind_CaM_Ca4_898_0__Kf * CaMKIII_1402_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaMKIII_bind_CaM_Ca4_898_0__Kb * CaMKIII_CaM_Ca4_1404_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaMKIII\_bind\_CaM\_Ca4\_898\_0\_\_Kf}\mathrm{CaMKIII\_1402\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaMKIII\_bind\_CaM\_Ca4\_898\_0\_\_Kb}\mathrm{CaMKIII\_CaM\_Ca4\_1404\_0\_}$ K inhib = 1nM from Cohen Ann Rev Bioch 1989, 4 nM from Foukes et al Assume 2 nM. kf /kb = 8.333e-4 595.588235294 212.048192771 white 11 kinetics_455_0_ * Inact_PP1_927_0__Kf * I1_p_921_0_*PP1_active_902_0_-kinetics_455_0_ * Inact_PP1_927_0__Kb * PP1_I1_p_923_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Inact\_PP1\_927\_0\_\_Kf}\mathrm{I1\_p\_921\_0\_}\mathrm{PP1\_active\_902\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Inact\_PP1\_927\_0\_\_Kb}\mathrm{PP1\_I1\_p\_923\_0\_}$ Let us assume that the equil in this case is very far over to the right. This is probably safe. 610.294117647 212.048192771 white 11 kinetics_455_0_ * dissoc_PP1_I1_929_0__Kf * PP1_I1_925_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dissoc\_PP1\_I1\_929\_0\_\_Kf}\mathrm{PP1\_I1\_925\_0\_}$ This process is probably much more complicated and involves CaM. However, as I can't find detailed info I am bundling this into a single step. Based on Steemer and Klee pg 6863, the Kact is 0.5 uM. kf/kb = 1/(0.5 * 6e5)^2 = 1.11e-11 742.647058824 212.048192771 white 12 kinetics_455_0_ * Ca_bind_CaNAB_Ca2_943_0__Kf * Ca_1174_0_^2*CaNAB_Ca2_935_0_-kinetics_455_0_ * Ca_bind_CaNAB_Ca2_943_0__Kb * CaNAB_Ca4_877_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_bind\_CaNAB\_Ca2\_943\_0\_\_Kf}\mathrm{Ca\_1174\_0\_}^2\mathrm{CaNAB\_Ca2\_935\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_bind\_CaNAB\_Ca2\_943\_0\_\_Kb}\mathrm{CaNAB\_Ca4\_877\_0\_}$ going on the experience with CaM, we put the fast (high affinity) sites first. We only know (Stemmer and Klee) that the affinity is _lessthan_ 70 nM. Assuming 10 nM at first, we get kf = 2.78e-8, kb = 1. Try 20 nM. kf = 7e-9, kb = 1 757.352941176 212.048192771 white 12 kinetics_455_0_ * Ca_bind_CaNAB_945_0__Kf * CaNAB_933_0_*Ca_1174_0_^2-kinetics_455_0_ * Ca_bind_CaNAB_945_0__Kb * CaNAB_Ca2_935_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_bind\_CaNAB\_945\_0\_\_Kf}\mathrm{CaNAB\_933\_0\_}\mathrm{Ca\_1174\_0\_}^2-\mathrm{kinetics\_455\_0\_}\mathrm{Ca\_bind\_CaNAB\_945\_0\_\_Kb}\mathrm{CaNAB\_Ca2\_935\_0\_}$ Disabled. See notes for PP2B7.g 772.058823529 212.048192771 white 12 kinetics_455_0_ * CaM_Ca2_bind_CaNAB_947_0__Kf * CaM_Ca2_882_0_*CaNAB_Ca4_877_0_-kinetics_455_0_ * CaM_Ca2_bind_CaNAB_947_0__Kb * CaMCa2_CaNAB_939_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca2\_bind\_CaNAB\_947\_0\_\_Kf}\mathrm{CaM\_Ca2\_882\_0\_}\mathrm{CaNAB\_Ca4\_877\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_Ca2\_bind\_CaNAB\_947\_0\_\_Kb}\mathrm{CaMCa2\_CaNAB\_939\_0\_}$ 786.764705882 212.048192771 white 12 kinetics_455_0_ * CaMCa3_bind_CaNAB_949_0__Kf * CaM_Ca3_864_0_*CaNAB_Ca4_877_0_-kinetics_455_0_ * CaMCa3_bind_CaNAB_949_0__Kb * CaMCa3_CaNAB_937_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaMCa3\_bind\_CaNAB\_949\_0\_\_Kf}\mathrm{CaM\_Ca3\_864\_0\_}\mathrm{CaNAB\_Ca4\_877\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaMCa3\_bind\_CaNAB\_949\_0\_\_Kb}\mathrm{CaMCa3\_CaNAB\_937\_0\_}$ 801.470588235 212.048192771 white 12 kinetics_455_0_ * CaMCa4_bind_CaNAB_951_0__Kf * CaNAB_Ca4_877_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaMCa4_bind_CaNAB_951_0__Kb * CaMCa4_CaNAB_941_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaMCa4\_bind\_CaNAB\_951\_0\_\_Kf}\mathrm{CaNAB\_Ca4\_877\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaMCa4\_bind\_CaNAB\_951\_0\_\_Kb}\mathrm{CaMCa4\_CaNAB\_941\_0\_}$ Hasler et al FASEB J 6:2734-2741 1992 say Kd =1e-7M for type II, 5.6e-8 M for type I. Take mean which comes to 2e-13 #/cell Smith et al PNAS USA 78:3 1591-1595 1981 have better data. First kf/kb=2.1e7/M = 3.5e-5 (#/cell). Ogreid and Doskeland Febs Lett 129:2 287-292 1981 have figs suggesting time course of complete assoc is _lessthan_ 1 min. 889.705882353 212.048192771 white 13 kinetics_455_0_ * cAMP_bind_site_B1_984_0__Kf * cAMP_1000_0_*R2C2_966_0_-kinetics_455_0_ * cAMP_bind_site_B1_984_0__Kb * R2C2_cAMP_968_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_B1\_984\_0\_\_Kf}\mathrm{cAMP\_1000\_0\_}\mathrm{R2C2\_966\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_B1\_984\_0\_\_Kb}\mathrm{R2C2\_cAMP\_968\_0\_}$ For now let us set this to the same Km (1e-7M) as site B. This gives kf/kb = .7e-7M * 1e6 / (6e5^2) : 1/(6e5^2) = 2e-13:2.77e-12 Smith et al have better values. They say that this is cooperative, so the consts are now kf/kb =8.3e-4 904.411764706 212.048192771 white 13 kinetics_455_0_ * cAMP_bind_site_B2_986_0__Kf * R2C2_cAMP_968_0_*cAMP_1000_0_-kinetics_455_0_ * cAMP_bind_site_B2_986_0__Kb * R2C2_cAMP2_970_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_B2\_986\_0\_\_Kf}\mathrm{R2C2\_cAMP\_968\_0\_}\mathrm{cAMP\_1000\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_B2\_986\_0\_\_Kb}\mathrm{R2C2\_cAMP2\_970\_0\_}$ 919.117647059 212.048192771 white 13 kinetics_455_0_ * cAMP_bind_site_A1_988_0__Kf * cAMP_1000_0_*R2C2_cAMP2_970_0_-kinetics_455_0_ * cAMP_bind_site_A1_988_0__Kb * R2C2_cAMP3_972_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_A1\_988\_0\_\_Kf}\mathrm{cAMP\_1000\_0\_}\mathrm{R2C2\_cAMP2\_970\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_A1\_988\_0\_\_Kb}\mathrm{R2C2\_cAMP3\_972\_0\_}$ 933.823529412 212.048192771 white 13 kinetics_455_0_ * cAMP_bind_site_A2_990_0__Kf * cAMP_1000_0_*R2C2_cAMP3_972_0_-kinetics_455_0_ * cAMP_bind_site_A2_990_0__Kb * R2C2_cAMP4_974_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_A2\_990\_0\_\_Kf}\mathrm{cAMP\_1000\_0\_}\mathrm{R2C2\_cAMP3\_972\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{cAMP\_bind\_site\_A2\_990\_0\_\_Kb}\mathrm{R2C2\_cAMP4\_974\_0\_}$ This has to be fast, as the activation of PKA by cAMP is also fast. kf was 10 948.529411765 212.048192771 white 13 kinetics_455_0_ * Release_C1_992_0__Kf * R2C2_cAMP4_974_0_-kinetics_455_0_ * Release_C1_992_0__Kb * R2C_cAMP4_976_0_*PKA_active_955_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Release\_C1\_992\_0\_\_Kf}\mathrm{R2C2\_cAMP4\_974\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Release\_C1\_992\_0\_\_Kb}\mathrm{R2C\_cAMP4\_976\_0\_}\mathrm{PKA\_active\_955\_0\_}$ 963.235294118 212.048192771 white 13 kinetics_455_0_ * Release_C2_994_0__Kf * R2C_cAMP4_976_0_-kinetics_455_0_ * Release_C2_994_0__Kb * R2_cAMP4_978_0_*PKA_active_955_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Release\_C2\_994\_0\_\_Kf}\mathrm{R2C\_cAMP4\_976\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Release\_C2\_994\_0\_\_Kb}\mathrm{R2\_cAMP4\_978\_0\_}\mathrm{PKA\_active\_955\_0\_}$ This has to be set to zero for matching the expts in vitro. In vivo we need to consider the inhibition though. kf = 1e-5 kb = 1 977.941176471 212.048192771 white 13 kinetics_455_0_ * inhib_PKA_996_0__Kf * PKA_active_955_0_*PKA_inhibitor_980_0_-kinetics_455_0_ * inhib_PKA_996_0__Kb * inhibited_PKA_982_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{inhib\_PKA\_996\_0\_\_Kf}\mathrm{PKA\_active\_955\_0\_}\mathrm{PKA\_inhibitor\_980\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{inhib\_PKA\_996\_0\_\_Kb}\mathrm{inhibited\_PKA\_982\_0\_}$ Half-max at 20 nM CaM (Tang et al JBC 266:13 8595-8603 1991 kb/kf = 20 nM = 12000 #/cell so kf = kb/12000 = kb * 8.333e-5 7.35294117647 404.819277108 white 14 kinetics_455_0_ * CaM_bind_AC1_1048_0__Kf * AC1_1008_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaM_bind_AC1_1048_0__Kb * AC1_CaM_1004_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_AC1\_1048\_0\_\_Kf}\mathrm{AC1\_1008\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_AC1\_1048\_0\_\_Kb}\mathrm{AC1\_CaM\_1004\_0\_}$ Random rate. 22.0588235294 404.819277108 white 14 kinetics_455_0_ * dephosph_AC2_1050_0__Kf * AC2_p_1010_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_AC2\_1050\_0\_\_Kf}\mathrm{AC2\_p\_1010\_0\_}$ Half-max at around 3nM = kb/kf from fig 5 in Feinstein et al PNAS USA 88 10173-10177 1991 kf = kb/1800 = 5.56e-4 kb Ofer's thesis data indicates it is more like 2 nM. kf = kb/1200 = 8.33e-4 36.7647058824 404.819277108 white 14 kinetics_455_0_ * Gs_bind_AC2_1052_0__Kf * Gs_alpha_1096_0_*AC2_1018_0_-kinetics_455_0_ * Gs_bind_AC2_1052_0__Kb * AC2_Gs_1014_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Gs\_bind\_AC2\_1052\_0\_\_Kf}\mathrm{Gs\_alpha\_1096\_0\_}\mathrm{AC2\_1018\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Gs\_bind\_AC2\_1052\_0\_\_Kb}\mathrm{AC2\_Gs\_1014\_0\_}$ Half-max 8nM from Tang et al JBC266:13 8595-8603 kb/kf = 8 nM = 4800#/cell so kf = kb * 2.08e-4 51.4705882353 404.819277108 white 14 kinetics_455_0_ * Gs_bind_AC1_1054_0__Kf * AC1_1008_0_*Gs_alpha_1096_0_-kinetics_455_0_ * Gs_bind_AC1_1054_0__Kb * AC1_Gs_1020_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Gs\_bind\_AC1\_1054\_0\_\_Kf}\mathrm{AC1\_1008\_0\_}\mathrm{Gs\_alpha\_1096\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Gs\_bind\_AC1\_1054\_0\_\_Kb}\mathrm{AC1\_Gs\_1020\_0\_}$ kb/kf = 1.2 nM so kf = kb/720 = 1.3888 * kb. 66.1764705882 404.819277108 white 14 kinetics_455_0_ * Gs_bind_AC2_p_1056_0__Kf * Gs_alpha_1096_0_*AC2_p_1010_0_-kinetics_455_0_ * Gs_bind_AC2_p_1056_0__Kb * AC2_p_Gs_1024_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Gs\_bind\_AC2\_p\_1056\_0\_\_Kf}\mathrm{Gs\_alpha\_1096\_0\_}\mathrm{AC2\_p\_1010\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Gs\_bind\_AC2\_p\_1056\_0\_\_Kb}\mathrm{AC2\_p\_Gs\_1024\_0\_}$ The rates for this are poorly constrained. In adipocytes (probably a different PDE) the dephosphorylation is complete within 15 min, but there are no intermediate time points so it could be much faster. Identity of phosphatase etc is still unknown. 80.8823529412 404.819277108 white 14 kinetics_455_0_ * dephosph_PDE_1058_0__Kf * cAMP_PDE_p_1033_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{dephosph\_PDE\_1058\_0\_\_Kf}\mathrm{cAMP\_PDE\_p\_1033\_0\_}$ For olf epi PDE1, affinity is 7 nM. Assume same for brain. Reaction should be pretty fast. Assume kb = 5/sec. Then kf = 5 / (0.007 * 6e5) = 1.2e-3 95.5882352941 404.819277108 white 14 kinetics_455_0_ * CaM_bind_PDE1_1060_0__Kf * PDE1_1038_0_*CaM_Ca4_854_0_-kinetics_455_0_ * CaM_bind_PDE1_1060_0__Kb * CaM_dot_PDE1_1043_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_PDE1\_1060\_0\_\_Kf}\mathrm{PDE1\_1038\_0\_}\mathrm{CaM\_Ca4\_854\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{CaM\_bind\_PDE1\_1060\_0\_\_Kb}\mathrm{CaM\_dot\_PDE1\_1043\_0\_}$ kf = kf from text = 1e7 / M / sec = 10 /uM/sec = 10 / 6e5 / # / sec = 1.67e-5 kb = kr from text = 60 / sec Note that we continue to use uM here since [phenylephrine] is also in uM. From Martin et al FEBS Lett 316:2 191-196 1993 we have Kd = 600 nM Assuming kb = 10/sec, we get kf = 10/(0.6 uM * 6e5) = 2.8e-5 1/sec/# 154.411764706 404.819277108 white 15 kinetics_455_0_ * RecLigandBinding_1076_0__Kf * Glutamate_1066_0_*mGluR_1068_0_-kinetics_455_0_ * RecLigandBinding_1076_0__Kb * Rec_Glu_1070_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{RecLigandBinding\_1076\_0\_\_Kf}\mathrm{Glutamate\_1066\_0\_}\mathrm{mGluR\_1068\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{RecLigandBinding\_1076\_0\_\_Kb}\mathrm{Rec\_Glu\_1070\_0\_}$ This is the k1-k2 equivalent for enzyme complex formation in the binding of Rec-Glu to Gq. See Fay et al Biochem 30 5066-5075 1991. kf = 5e-5 which is nearly the same as calculated by Fay et al. (4.67e-5) kb = .04 June 1996: Closer reading of Fay et al suggests that kb _lessthan_= 0.0001, so kf = 1e-8 by detailed balance. This reaction appears to be neglible. 169.117647059 404.819277108 white 15 kinetics_455_0_ * Rec_Glu_bind_Gq_1078_0__Kf * G_GDP_1094_0_*Rec_Glu_1070_0_-kinetics_455_0_ * Rec_Glu_bind_Gq_1078_0__Kb * Rec_Glu_Gq_1074_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Rec\_Glu\_bind\_Gq\_1078\_0\_\_Kf}\mathrm{G\_GDP\_1094\_0\_}\mathrm{Rec\_Glu\_1070\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Rec\_Glu\_bind\_Gq\_1078\_0\_\_Kb}\mathrm{Rec\_Glu\_Gq\_1074\_0\_}$ From Fay et al kb3 = kb = 1.06e-3 which is rather slow. k+1 = kf = 2.8e7 /M/sec= 4.67e-5/sec use 5e-5. However, the Kd from Martin et al may be more appropriate, as this is Glu not the system from Fay. kf = 2.8e-5, kb = 10 Let us compromise. since we have the Fay model, keep kf = k+1 = 2.8e-5. But kb (k-3) is .01 * k-1 from Fay. Scaling by .01, kb = .01 * 10 = 0.1 183.823529412 404.819277108 white 15 kinetics_455_0_ * Glu_bind_Rec_Gq_1080_0__Kf * Rec_Gq_1072_0_*Glutamate_1066_0_-kinetics_455_0_ * Glu_bind_Rec_Gq_1080_0__Kb * Rec_Glu_Gq_1074_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Glu\_bind\_Rec\_Gq\_1080\_0\_\_Kf}\mathrm{Rec\_Gq\_1072\_0\_}\mathrm{Glutamate\_1066\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Glu\_bind\_Rec\_Gq\_1080\_0\_\_Kb}\mathrm{Rec\_Glu\_Gq\_1074\_0\_}$ This is the kcat==k3 stage of the Rec-Glu ezymatic activation of Gq. From Berstein et al actiation is at .35 - 0.7/min From Fay et al Biochem 30 5066-5075 1991 kf = .01/sec From Nakamura et al J physiol Lond 474:1 35-41 1994 see time courses. Also (Berstein) 15-40% of gprot is in GTP-bound form on stim. 198.529411765 404.819277108 white 15 kinetics_455_0_ * Activate_Gq_1082_0__Kf * Rec_Glu_Gq_1074_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Activate\_Gq\_1082\_0\_\_Kf}\mathrm{Rec\_Glu\_Gq\_1074\_0\_}$ Lets try out the same kinetics as the Rec-Glu-bind-Gq This is much too forward. We know that the steady-state amount of Rec-Gq should be 40% of the total amount of receptor. This is for a different receptor, still we can try to match the value. kf = 1e-6 and kb = 1 give 0.333:0.8 which is pretty close. 213.235294118 404.819277108 white 15 kinetics_455_0_ * Rec_bind_Gq_1084_0__Kf * mGluR_1068_0_*G_GDP_1094_0_-kinetics_455_0_ * Rec_bind_Gq_1084_0__Kb * Rec_Gq_1072_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Rec\_bind\_Gq\_1084\_0\_\_Kf}\mathrm{mGluR\_1068\_0\_}\mathrm{G\_GDP\_1094\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Rec\_bind\_Gq\_1084\_0\_\_Kb}\mathrm{Rec\_Gq\_1072\_0\_}$ kf = kg1 = 0.01/sec, kb = 0. This is the basal exchange of GTP for GDP. 301.470588235 404.819277108 white 16 kinetics_455_0_ * Basal_Act_Gq_1098_0__Kf * G_GDP_1094_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Basal\_Act\_Gq\_1098\_0\_\_Kf}\mathrm{G\_GDP\_1094\_0\_}$ kf == kg3 = 1e-5 /cell/sec. As usual, there is no back-reaction kb = 0 316.176470588 404.819277108 white 16 kinetics_455_0_ * Trimerize_G_1100_0__Kf * BetaGamma_1088_0_*G_pGDP_1092_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Trimerize\_G\_1100\_0\_\_Kf}\mathrm{BetaGamma\_1088\_0\_}\mathrm{G\_pGDP\_1092\_0\_}$ From Berstein et al JBC 267:12 8081-8088 1992, kcat for GTPase activity of Gq is only 0.8/min 330.882352941 404.819277108 white 16 kinetics_455_0_ * Inact_Gq_1102_0__Kf * G_pGTP_1090_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Inact\_Gq\_1102\_0\_\_Kf}\mathrm{G\_pGTP\_1090\_0\_}$ 742.647058824 404.819277108 white 19 kinetics_455_0_ * bind_Gab1_1208_0__Kf * Gab1_1199_0_*SHC_p_Grb2_clx_775_0_-kinetics_455_0_ * bind_Gab1_1208_0__Kb * SHC_p_Grb2_Gab1_clx_1201_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{bind\_Gab1\_1208\_0\_\_Kf}\mathrm{Gab1\_1199\_0\_}\mathrm{SHC\_p\_Grb2\_clx\_775\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{bind\_Gab1\_1208\_0\_\_Kb}\mathrm{SHC\_p\_Grb2\_Gab1\_clx\_1201\_0\_}$ 757.352941176 404.819277108 white 19 kinetics_455_0_ * PI3K_act_1210_0__Kf * PI3K_1192_0_*SHC_p_Grb2_Gab1_clx_1201_0_-kinetics_455_0_ * PI3K_act_1210_0__Kb * SHC_p_Grb2_Gab1_PI3K_clx_1187_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PI3K\_act\_1210\_0\_\_Kf}\mathrm{PI3K\_1192\_0\_}\mathrm{SHC\_p\_Grb2\_Gab1\_clx\_1201\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PI3K\_act\_1210\_0\_\_Kb}\mathrm{SHC\_p\_Grb2\_Gab1\_PI3K\_clx\_1187\_0\_}$ 772.058823529 404.819277108 white 19 kinetics_455_0_ * basal_PI3K_act_1212_0__Kf * PI3K_1192_0_-kinetics_455_0_ * basal_PI3K_act_1212_0__Kb * PI3K_basal_1194_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{basal\_PI3K\_act\_1212\_0\_\_Kf}\mathrm{PI3K\_1192\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{basal\_PI3K\_act\_1212\_0\_\_Kb}\mathrm{PI3K\_basal\_1194\_0\_}$ 823.529411765 404.819277108 white 19 kinetics_455_0_ * PI3K_bind_Ras_GTP_1219_0__Kf * PI3K_1192_0_*GTP_Ras_702_0_-kinetics_455_0_ * PI3K_bind_Ras_GTP_1219_0__Kb * Ras_GTP_PI3K_1214_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PI3K\_bind\_Ras\_GTP\_1219\_0\_\_Kf}\mathrm{PI3K\_1192\_0\_}\mathrm{GTP\_Ras\_702\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PI3K\_bind\_Ras\_GTP\_1219\_0\_\_Kb}\mathrm{Ras\_GTP\_PI3K\_1214\_0\_}$ 889.705882353 404.819277108 white 20 kinetics_455_0_ * PIP3_bind_AKT_1247_0__Kf * PIP3_1180_0_*AKT_1245_0_-kinetics_455_0_ * PIP3_bind_AKT_1247_0__Kb * PIP3_AKT_1223_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PIP3\_bind\_AKT\_1247\_0\_\_Kf}\mathrm{PIP3\_1180\_0\_}\mathrm{AKT\_1245\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PIP3\_bind\_AKT\_1247\_0\_\_Kb}\mathrm{PIP3\_AKT\_1223\_0\_}$ 904.411764706 404.819277108 white 20 kinetics_455_0_ * PIP3_bind_PDK1_1249_0__Kf * PIP3_1180_0_*PDK1_1182_0_-kinetics_455_0_ * PIP3_bind_PDK1_1249_0__Kb * PIP3_PDK1_1225_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{PIP3\_bind\_PDK1\_1249\_0\_\_Kf}\mathrm{PIP3\_1180\_0\_}\mathrm{PDK1\_1182\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{PIP3\_bind\_PDK1\_1249\_0\_\_Kb}\mathrm{PIP3\_PDK1\_1225\_0\_}$ 7.35294117647 597.590361446 white 21 kinetics_455_0_ * Autophos_TrKB_1269_0__Kf * BDNF_TrKB2_clx_1257_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Autophos\_TrKB\_1269\_0\_\_Kf}\mathrm{BDNF\_TrKB2\_clx\_1257\_0\_}$ 22.0588235294 597.590361446 white 21 kinetics_455_0_ * Dimeriz_TrKB_1271_0__Kf * BDNF_TrKB_clx_1259_0_*TrKB_1255_0_-kinetics_455_0_ * Dimeriz_TrKB_1271_0__Kb * BDNF_TrKB2_clx_1257_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Dimeriz\_TrKB\_1271\_0\_\_Kf}\mathrm{BDNF\_TrKB\_clx\_1259\_0\_}\mathrm{TrKB\_1255\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Dimeriz\_TrKB\_1271\_0\_\_Kb}\mathrm{BDNF\_TrKB2\_clx\_1257\_0\_}$ 36.7647058824 597.590361446 white 21 kinetics_455_0_ * Ligand_binding_1273_0__Kf * BDNF_1398_0_*TrKB_1255_0_-kinetics_455_0_ * Ligand_binding_1273_0__Kb * BDNF_TrKB_clx_1259_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Ligand\_binding\_1273\_0\_\_Kf}\mathrm{BDNF\_1398\_0\_}\mathrm{TrKB\_1255\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Ligand\_binding\_1273\_0\_\_Kb}\mathrm{BDNF\_TrKB\_clx\_1259\_0\_}$ 51.4705882353 597.590361446 white 21 kinetics_455_0_ * LR_Internalize_1275_0__Kf * BDNF_TrKB2_p_clx_1261_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{LR\_Internalize\_1275\_0\_\_Kf}\mathrm{BDNF\_TrKB2\_p\_clx\_1261\_0\_}$ 66.1764705882 597.590361446 white 21 kinetics_455_0_ * LR_cycling_1277_0__Kf * Int_BDNF_TrKB2_p_clx_1253_0_-kinetics_455_0_ * LR_cycling_1277_0__Kb * TrKB_1255_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{LR\_cycling\_1277\_0\_\_Kf}\mathrm{Int\_BDNF\_TrKB2\_p\_clx\_1253\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{LR\_cycling\_1277\_0\_\_Kb}\mathrm{TrKB\_1255\_0\_}$ 154.411764706 597.590361446 white 22 kinetics_455_0_ * Rheb_GTP_bind_TORclx_1298_0__Kf * Rheb_GTP_1281_0_*TOR_clx_1285_0_-kinetics_455_0_ * Rheb_GTP_bind_TORclx_1298_0__Kb * TOR_Rheb_GTP_clx_1287_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Rheb\_GTP\_bind\_TORclx\_1298\_0\_\_Kf}\mathrm{Rheb\_GTP\_1281\_0\_}\mathrm{TOR\_clx\_1285\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Rheb\_GTP\_bind\_TORclx\_1298\_0\_\_Kb}\mathrm{TOR\_Rheb\_GTP\_clx\_1287\_0\_}$ 169.117647059 597.590361446 white 22 kinetics_455_0_ * GDP_to_GTP_1300_0__Kf * Rheb_GDP_1283_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{GDP\_to\_GTP\_1300\_0\_\_Kf}\mathrm{Rheb\_GDP\_1283\_0\_}$ 301.470588235 597.590361446 white 23 kinetics_455_0_ * S6_dephosph_1326_0__Kf * _40S_1474_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{S6\_dephosph\_1326\_0\_\_Kf}\mathrm{\_40S\_1474\_0\_}$ 316.176470588 597.590361446 white 23 kinetics_455_0_ * basal_S6K_1328_0__Kf * S6K_1306_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{basal\_S6K\_1328\_0\_\_Kf}\mathrm{S6K\_1306\_0\_}$ 448.529411765 597.590361446 white 24 kinetics_455_0_ * eIF4E_bind_BP2_1344_0__Kf * eIF4E_1420_0_*_4E_BP_1332_0_-kinetics_455_0_ * eIF4E_bind_BP2_1344_0__Kb * eIF4E_BP_1336_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{eIF4E\_bind\_BP2\_1344\_0\_\_Kf}\mathrm{eIF4E\_1420\_0\_}\mathrm{\_4E\_BP\_1332\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{eIF4E\_bind\_BP2\_1344\_0\_\_Kb}\mathrm{eIF4E\_BP\_1336\_0\_}$ 463.235294118 597.590361446 white 24 kinetics_455_0_ * eIF4E_BP2_disso_1346_0__Kf * eIF4E_BP_t37_46_s65_1340_0_-kinetics_455_0_ * eIF4E_BP2_disso_1346_0__Kb * eIF4E_1420_0_*_4E_BP_t37_46_s65_1334_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{eIF4E\_BP2\_disso\_1346\_0\_\_Kf}\mathrm{eIF4E\_BP\_t37\_46\_s65\_1340\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{eIF4E\_BP2\_disso\_1346\_0\_\_Kb}\mathrm{eIF4E\_1420\_0\_}\mathrm{\_4E\_BP\_t37\_46\_s65\_1334\_0\_}$ 477.941176471 597.590361446 white 24 kinetics_455_0_ * eIF4E_BP_disso_1348_0__Kf * eIF4E_BP_thr37_46_1338_0_-kinetics_455_0_ * eIF4E_BP_disso_1348_0__Kb * eIF4E_1420_0_*_4E_BP_t37_46_1342_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{eIF4E\_BP\_disso\_1348\_0\_\_Kf}\mathrm{eIF4E\_BP\_thr37\_46\_1338\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{eIF4E\_BP\_disso\_1348\_0\_\_Kb}\mathrm{eIF4E\_1420\_0\_}\mathrm{\_4E\_BP\_t37\_46\_1342\_0\_}$ 595.588235294 597.590361446 white 25 kinetics_455_0_ * Q_binds_R_1360_0__Kf * _40S_1474_0_*Quaternary_clx_1356_0_-kinetics_455_0_ * Q_binds_R_1360_0__Kb * Q_dot_R_1352_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{Q\_binds\_R\_1360\_0\_\_Kf}\mathrm{\_40S\_1474\_0\_}\mathrm{Quaternary\_clx\_1356\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{Q\_binds\_R\_1360\_0\_\_Kb}\mathrm{Q\_dot\_R\_1352\_0\_}$ 610.294117647 597.590361446 white 25 kinetics_455_0_ * QR_binds_M_1362_0__Kf * Q_dot_R_1352_0_*eIF4F_mRNA_clx_1432_0_-kinetics_455_0_ * QR_binds_M_1362_0__Kb * _43Scomplex_1358_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{QR\_binds\_M\_1362\_0\_\_Kf}\mathrm{Q\_dot\_R\_1352\_0\_}\mathrm{eIF4F\_mRNA\_clx\_1432\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{QR\_binds\_M\_1362\_0\_\_Kb}\mathrm{\_43Scomplex\_1358\_0\_}$ 625.0 597.590361446 white 25 kinetics_455_0_ * R_binds_M_1364_0__Kf * eIF4F_mRNA_clx_1432_0_*_40S_1474_0_-kinetics_455_0_ * R_binds_M_1364_0__Kb * RM_1354_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{R\_binds\_M\_1364\_0\_\_Kf}\mathrm{eIF4F\_mRNA\_clx\_1432\_0\_}\mathrm{\_40S\_1474\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{R\_binds\_M\_1364\_0\_\_Kb}\mathrm{RM\_1354\_0\_}$ 639.705882353 597.590361446 white 25 kinetics_455_0_ * RM_binds_Q_1366_0__Kf * RM_1354_0_*Quaternary_clx_1356_0_-kinetics_455_0_ * RM_binds_Q_1366_0__Kb * _43Scomplex_1358_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{RM\_binds\_Q\_1366\_0\_\_Kf}\mathrm{RM\_1354\_0\_}\mathrm{Quaternary\_clx\_1356\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{RM\_binds\_Q\_1366\_0\_\_Kb}\mathrm{\_43Scomplex\_1358\_0\_}$ 742.647058824 597.590361446 white 26 kinetics_455_0_ * pep_elongation_1386_0__Kf * peptide_1372_0_-kinetics_455_0_ * pep_elongation_1386_0__Kb * protein_1376_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{pep\_elongation\_1386\_0\_\_Kf}\mathrm{peptide\_1372\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{pep\_elongation\_1386\_0\_\_Kb}\mathrm{protein\_1376\_0\_}$ 757.352941176 597.590361446 white 26 kinetics_455_0_ * protein_deg_1388_0__Kf * protein_1376_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{protein\_deg\_1388\_0\_\_Kf}\mathrm{protein\_1376\_0\_}$ 772.058823529 597.590361446 white 26 kinetics_455_0_ * rad_pep_elongation_1390_0__Kf * rad_peptide_1380_0_-kinetics_455_0_ * rad_pep_elongation_1390_0__Kb * rad_protein_1382_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{rad\_pep\_elongation\_1390\_0\_\_Kf}\mathrm{rad\_peptide\_1380\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{rad\_pep\_elongation\_1390\_0\_\_Kb}\mathrm{rad\_protein\_1382\_0\_}$ 786.764705882 597.590361446 white 26 kinetics_455_0_ * rad_protein_deg_1392_0__Kf * rad_protein_1382_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{rad\_protein\_deg\_1392\_0\_\_Kf}\mathrm{rad\_protein\_1382\_0\_}$ 801.470588235 597.590361446 white 26 kinetics_455_0_ * labelling_1394_0__Kf * AA_1370_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{labelling\_1394\_0\_\_Kf}\mathrm{AA\_1370\_0\_}$ 7.35294117647 790.361445783 white 28 kinetics_455_0_ * CaMKIII_dephospho_1416_0__Kf * CaMKIII_p_1414_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{CaMKIII\_dephospho\_1416\_0\_\_Kf}\mathrm{CaMKIII\_p\_1414\_0\_}$ 154.411764706 790.361445783 white 29 kinetics_455_0_ * eIF4F_clx_1434_0__Kf * eIF4E_1420_0_*eIF4G_A_clx_1422_0_-kinetics_455_0_ * eIF4F_clx_1434_0__Kb * eIF4F_1428_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{eIF4F\_clx\_1434\_0\_\_Kf}\mathrm{eIF4E\_1420\_0\_}\mathrm{eIF4G\_A\_clx\_1422\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{eIF4F\_clx\_1434\_0\_\_Kb}\mathrm{eIF4F\_1428\_0\_}$ 169.117647059 790.361445783 white 29 kinetics_455_0_ * eIF4G_A_clx_formation_1436_0__Kf * eIF4A_1424_0_*eIF4G_1426_0_-kinetics_455_0_ * eIF4G_A_clx_formation_1436_0__Kb * eIF4G_A_clx_1422_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{eIF4G\_A\_clx\_formation\_1436\_0\_\_Kf}\mathrm{eIF4A\_1424\_0\_}\mathrm{eIF4G\_1426\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{eIF4G\_A\_clx\_formation\_1436\_0\_\_Kb}\mathrm{eIF4G\_A\_clx\_1422\_0\_}$ 183.823529412 790.361445783 white 29 kinetics_455_0_ * eIF4F_mRNA_clx_formation_1438_0__Kf * eIF4F_1428_0_*mRNA_1430_0_-kinetics_455_0_ * eIF4F_mRNA_clx_formation_1438_0__Kb * eIF4F_mRNA_clx_1432_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{eIF4F\_mRNA\_clx\_formation\_1438\_0\_\_Kf}\mathrm{eIF4F\_1428\_0\_}\mathrm{mRNA\_1430\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{eIF4F\_mRNA\_clx\_formation\_1438\_0\_\_Kb}\mathrm{eIF4F\_mRNA\_clx\_1432\_0\_}$ 301.470588235 790.361445783 white 30 kinetics_455_0_ * elongation_1466_0__Kf * _80S_ribos_clx_1456_0_*eEF2_1442_0_-kinetics_455_0_ * elongation_1466_0__Kb * Translation_clx_1448_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{elongation\_1466\_0\_\_Kf}\mathrm{\_80S\_ribos\_clx\_1456\_0\_}\mathrm{eEF2\_1442\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{elongation\_1466\_0\_\_Kb}\mathrm{Translation\_clx\_1448\_0\_}$ 316.176470588 790.361445783 white 30 kinetics_455_0_ * activation_1468_0__Kf * _60S_R_1446_0_*_43Scomplex_1358_0_-kinetics_455_0_ * activation_1468_0__Kb * _80S_ribos_clx_1456_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{activation\_1468\_0\_\_Kf}\mathrm{\_60S\_R\_1446\_0\_}\mathrm{\_43Scomplex\_1358\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{activation\_1468\_0\_\_Kb}\mathrm{\_80S\_ribos\_clx\_1456\_0\_}$ 595.588235294 790.361445783 white 32 kinetics_455_0_ * TSC1_TSC2_dephospho_1490_0__Kf * TSC1_TSC2_p_1483_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{TSC1\_TSC2\_dephospho\_1490\_0\_\_Kf}\mathrm{TSC1\_TSC2\_p\_1483\_0\_}$ 742.647058824 790.361445783 white 33 kinetics_455_0_ * L_dot_mGluR_HomerBinding_1507_0__Kf * Homer_1494_0_*Rec_Glu_1070_0_-kinetics_455_0_ * L_dot_mGluR_HomerBinding_1507_0__Kb * L_dot_mGluR_p_dot_Homer_1496_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{L\_dot\_mGluR\_HomerBinding\_1507\_0\_\_Kf}\mathrm{Homer\_1494\_0\_}\mathrm{Rec\_Glu\_1070\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{L\_dot\_mGluR\_HomerBinding\_1507\_0\_\_Kb}\mathrm{L\_dot\_mGluR\_p\_dot\_Homer\_1496\_0\_}$ 757.352941176 790.361445783 white 33 kinetics_455_0_ * L_dot_mGluR_dot_Homer_PIKE_Binding_1509_0__Kf * L_dot_mGluR_p_dot_Homer_1496_0_*PIKE_L_1500_0_-kinetics_455_0_ * L_dot_mGluR_dot_Homer_PIKE_Binding_1509_0__Kb * L_dot_mGluR_p_dot_Homer_dot_PIKE_L_1498_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{L\_dot\_mGluR\_dot\_Homer\_PIKE\_Binding\_1509\_0\_\_Kf}\mathrm{L\_dot\_mGluR\_p\_dot\_Homer\_1496\_0\_}\mathrm{PIKE\_L\_1500\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{L\_dot\_mGluR\_dot\_Homer\_PIKE\_Binding\_1509\_0\_\_Kb}\mathrm{L\_dot\_mGluR\_p\_dot\_Homer\_dot\_PIKE\_L\_1498\_0\_}$ 772.058823529 790.361445783 white 33 kinetics_455_0_ * L_dot_mGluR_dot_Homer_dot_PIKE_PI3K_Binding_1511_0__Kf * PI3K_1192_0_*L_dot_mGluR_p_dot_Homer_dot_PIKE_L_1498_0_-kinetics_455_0_ * L_dot_mGluR_dot_Homer_dot_PIKE_PI3K_Binding_1511_0__Kb * L_dot_mGluR_p_dot_Homer_dot_PIKE_L_dot_PI3K_1502_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{L\_dot\_mGluR\_dot\_Homer\_dot\_PIKE\_PI3K\_Binding\_1511\_0\_\_Kf}\mathrm{PI3K\_1192\_0\_}\mathrm{L\_dot\_mGluR\_p\_dot\_Homer\_dot\_PIKE\_L\_1498\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{L\_dot\_mGluR\_dot\_Homer\_dot\_PIKE\_PI3K\_Binding\_1511\_0\_\_Kb}\mathrm{L\_dot\_mGluR\_p\_dot\_Homer\_dot\_PIKE\_L\_dot\_PI3K\_1502\_0\_}$ Heitzler,2012 889.705882353 790.361445783 white 34 kinetics_455_0_ * mGluR_barr2_assoc_1534_0__Kf * L_dot_mGluR_p_1520_0_*barr2_1522_0_-kinetics_455_0_ * mGluR_barr2_assoc_1534_0__Kb * L_dot_mGluR_p_dot_barr2_1526_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{mGluR\_barr2\_assoc\_1534\_0\_\_Kf}\mathrm{L\_dot\_mGluR\_p\_1520\_0\_}\mathrm{barr2\_1522\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{mGluR\_barr2\_assoc\_1534\_0\_\_Kb}\mathrm{L\_dot\_mGluR\_p\_dot\_barr2\_1526\_0\_}$ Rate based on internalization time after beta-arrestin binding. According to Mundell SJ et al., 2001, t(1/2) ~ 1.9(+/-)0.4 min. Therefore, kf =0.005 to 0.0077/s 904.411764706 790.361445783 white 34 kinetics_455_0_ * mGluR_internalize_1536_0__Kf * mGluR_p_dot_barr2_1532_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{mGluR\_internalize\_1536\_0\_\_Kf}\mathrm{mGluR\_p\_dot\_barr2\_1532\_0\_}$ 919.117647059 790.361445783 white 34 kinetics_455_0_ * barr2_dissoc_1538_0__Kf * Internal_mGluR_p_dot_barr2_1524_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{barr2\_dissoc\_1538\_0\_\_Kf}\mathrm{Internal\_mGluR\_p\_dot\_barr2\_1524\_0\_}$ 933.823529412 790.361445783 white 34 kinetics_455_0_ * mGluR_recycling_1540_0__Kf * Internal_mGluR_1528_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{mGluR\_recycling\_1540\_0\_\_Kf}\mathrm{Internal\_mGluR\_1528\_0\_}$ Navarro DL et al., Amino Acids (2005). Kd for glutamte-mGluR for rat fetus is 599 (+/-) 89.7 nM and for mothers is 534.3 (+/-) 89.7 nM. Therefore, assuming Kd = 595nM 948.529411765 790.361445783 white 34 kinetics_455_0_ * ligand_dissoc_1542_0__Kf * L_dot_mGluR_p_dot_barr2_1526_0_-kinetics_455_0_ * ligand_dissoc_1542_0__Kb * Glutamate_1066_0_*mGluR_p_dot_barr2_1532_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{ligand\_dissoc\_1542\_0\_\_Kf}\mathrm{L\_dot\_mGluR\_p\_dot\_barr2\_1526\_0\_}-\mathrm{kinetics\_455\_0\_}\mathrm{ligand\_dissoc\_1542\_0\_\_Kb}\mathrm{Glutamate\_1066\_0\_}\mathrm{mGluR\_p\_dot\_barr2\_1532\_0\_}$ Rate consts from Chen et al Biochem 32, 1032 (1993) k3 = k2 = 4 k1 = 9e-5 recalculated gives 1.666e-5, which is not very different. Looks like k3 is rate-limiting in this case: there is a huge amount of craf locked up in the enz complex. Let us assume a 10x higher Km, ie, lower affinity. k1 drops by 10x. Also changed k2 to 4x k3. Lowerd k1 to 1e-6 to balance 10X DAG sensitivity of PKC PKC_active_486_0_ craf_1_645_0_ PKC_act_raf_cplx_489_0_ PKC_act_raf_488_0_ 1 66.1764705882 125.301204819 yellow red kinetics_455_0_ * ( k1 * craf_1_645_0_*PKC_active_486_0_ - k2 * PKC_act_raf_cplx_489_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{craf\_1\_645\_0\_}\mathrm{PKC\_active\_486\_0\_}-\mathrm{k2}\mathrm{PKC\_act\_raf\_cplx\_489\_0\_})$ PKC_act_raf_cplx_489_0_ PKC_active_486_0_ craf_1_p_647_0_ PKC_act_raf_488_0_ 2 66.1764705882 125.301204819 yellow red kinetics_455_0_ * k3*PKC_act_raf_cplx_489_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKC\_act\_raf\_cplx\_489\_0\_}$ Rate consts copied from PCK-act-raf This reaction inactivates GAP. The idea is from the Boguski and McCormick review. PKC_active_486_0_ GAP_708_0_ PKC_inact_GAP_cplx_492_0_ PKC_inact_GAP_491_0_ 1 66.1764705882 115.662650602 yellow red kinetics_455_0_ * ( k1 * GAP_708_0_*PKC_active_486_0_ - k2 * PKC_inact_GAP_cplx_492_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GAP\_708\_0\_}\mathrm{PKC\_active\_486\_0\_}-\mathrm{k2}\mathrm{PKC\_inact\_GAP\_cplx\_492\_0\_})$ PKC_inact_GAP_cplx_492_0_ PKC_active_486_0_ GAP_p_706_0_ PKC_inact_GAP_491_0_ 2 66.1764705882 115.662650602 yellow red kinetics_455_0_ * k3*PKC_inact_GAP_cplx_492_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKC\_inact\_GAP\_cplx\_492\_0\_}$ Rate consts from PKC-act-raf. This reaction activates GEF. It can lead to at least 2X stim of ras, and a 2X stim of MAPK over and above that obtained via direct phosph of c-raf. Note that it is a push-pull reaction, and there is also a contribution through the phosphorylation and inactivation of GAPs. The original PKC-act-raf rate consts are too fast. We lower K1 by 10 X PKC_active_486_0_ inact_GEF_692_0_ PKC_act_GEF_cplx_495_0_ PKC_act_GEF_494_0_ 1 66.1764705882 106.024096386 yellow red kinetics_455_0_ * ( k1 * inact_GEF_692_0_*PKC_active_486_0_ - k2 * PKC_act_GEF_cplx_495_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{inact\_GEF\_692\_0\_}\mathrm{PKC\_active\_486\_0\_}-\mathrm{k2}\mathrm{PKC\_act\_GEF\_cplx\_495\_0\_})$ PKC_act_GEF_cplx_495_0_ PKC_active_486_0_ GEF_p_697_0_ PKC_act_GEF_494_0_ 2 66.1764705882 106.024096386 yellow red kinetics_455_0_ * k3*PKC_act_GEF_cplx_495_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKC\_act\_GEF\_cplx\_495\_0\_}$ Rates from Huang et al ABB 305:2 570-580 1993 PKC_active_486_0_ neurogranin_862_0_ PKC_phosph_neurogranin_cplx_498_0_ PKC_phosph_neurogranin_497_0_ 1 66.1764705882 96.3855421687 red red kinetics_455_0_ * ( k1 * neurogranin_862_0_*PKC_active_486_0_ - k2 * PKC_phosph_neurogranin_cplx_498_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{neurogranin\_862\_0\_}\mathrm{PKC\_active\_486\_0\_}-\mathrm{k2}\mathrm{PKC\_phosph\_neurogranin\_cplx\_498\_0\_})$ PKC_phosph_neurogranin_cplx_498_0_ PKC_active_486_0_ neurogranin_p_860_0_ PKC_phosph_neurogranin_497_0_ 2 66.1764705882 96.3855421687 red red kinetics_455_0_ * k3*PKC_phosph_neurogranin_cplx_498_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKC\_phosph\_neurogranin\_cplx\_498\_0\_}$ Rates are 60% those of PKC-phosph-neurogranin. See Huang et al ABB 305:2 570-580 1993 PKC_active_486_0_ neurogranin_CaM_858_0_ PKC_phosph_ng_CaM_cplx_501_0_ PKC_phosph_ng_CaM_500_0_ 1 66.1764705882 86.7469879518 red red kinetics_455_0_ * ( k1 * neurogranin_CaM_858_0_*PKC_active_486_0_ - k2 * PKC_phosph_ng_CaM_cplx_501_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{neurogranin\_CaM\_858\_0\_}\mathrm{PKC\_active\_486\_0\_}-\mathrm{k2}\mathrm{PKC\_phosph\_ng\_CaM\_cplx\_501\_0\_})$ PKC_phosph_ng_CaM_cplx_501_0_ PKC_active_486_0_ CaM_856_0_ neurogranin_p_860_0_ PKC_phosph_ng_CaM_500_0_ 2 66.1764705882 86.7469879518 red red kinetics_455_0_ * k3*PKC_phosph_ng_CaM_cplx_501_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKC\_phosph\_ng\_CaM\_cplx\_501\_0\_}$ Phorbol esters have little effect on AC1 or on the Gs-stimulation of AC2. So in this model we are only dealing with the increase in basal activation of AC2 induced by PKC k1 = 1.66e-6 k2 = 16 k3 =4 PKC_active_486_0_ AC2_1018_0_ phosph_AC2_cplx_504_0_ phosph_AC2_503_0_ 1 66.1764705882 77.1084337349 red red kinetics_455_0_ * ( k1 * AC2_1018_0_*PKC_active_486_0_ - k2 * phosph_AC2_cplx_504_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{AC2\_1018\_0\_}\mathrm{PKC\_active\_486\_0\_}-\mathrm{k2}\mathrm{phosph\_AC2\_cplx\_504\_0\_})$ phosph_AC2_cplx_504_0_ PKC_active_486_0_ AC2_p_1010_0_ phosph_AC2_503_0_ 2 66.1764705882 77.1084337349 red red kinetics_455_0_ * k3*phosph_AC2_cplx_504_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{phosph\_AC2\_cplx\_504\_0\_}$ 10 x raise oct22 12 x oct 24, set k2 = 4 * k3 PLA2_Ca_p_530_0_ APC_550_0_ kenz_cplx_533_0_ kenz_532_0_ 1 161.764705882 19.2771084337 yellow red kinetics_455_0_ * ( k1 * PLA2_Ca_p_530_0_*APC_550_0_ - k2 * kenz_cplx_533_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PLA2\_Ca\_p\_530\_0\_}\mathrm{APC\_550\_0\_}-\mathrm{k2}\mathrm{kenz\_cplx\_533\_0\_})$ kenz_cplx_533_0_ PLA2_Ca_p_530_0_ Arachidonic_Acid_573_0_ kenz_532_0_ 2 161.764705882 19.2771084337 yellow red kinetics_455_0_ * k3*kenz_cplx_533_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{kenz\_cplx\_533\_0\_}$ 10 X raise oct 22 12 X further raise oct 24 to allow for correct conc of enzyme PIP2_PLA2_p_535_0_ APC_550_0_ kenz_cplx_538_0_ kenz_537_0_ 1 176.470588235 19.2771084337 cyan red kinetics_455_0_ * ( k1 * APC_550_0_*PIP2_PLA2_p_535_0_ - k2 * kenz_cplx_538_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{APC\_550\_0\_}\mathrm{PIP2\_PLA2\_p\_535\_0\_}-\mathrm{k2}\mathrm{kenz\_cplx\_538\_0\_})$ kenz_cplx_538_0_ PIP2_PLA2_p_535_0_ Arachidonic_Acid_573_0_ kenz_537_0_ 2 176.470588235 19.2771084337 cyan red kinetics_455_0_ * k3*kenz_cplx_538_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{kenz\_cplx\_538\_0\_}$ 10 x raise oct 22 12 x and rescale for k2 = 4 * k3 convention oct 24 Increase further to get the match to expt, which was spoilt due to large accumulation of PLA2 in the enzyme complexed forms. Lets raise k3, leaving the others at k1 = 1.5e-5 and k2 = 144 since they are large already. PIP2_Ca_PLA2_p_540_0_ APC_550_0_ kenz_cplx_543_0_ kenz_542_0_ 1 191.176470588 19.2771084337 cyan red kinetics_455_0_ * ( k1 * PIP2_Ca_PLA2_p_540_0_*APC_550_0_ - k2 * kenz_cplx_543_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP2\_Ca\_PLA2\_p\_540\_0\_}\mathrm{APC\_550\_0\_}-\mathrm{k2}\mathrm{kenz\_cplx\_543\_0\_})$ kenz_cplx_543_0_ PIP2_Ca_PLA2_p_540_0_ Arachidonic_Acid_573_0_ kenz_542_0_ 2 191.176470588 19.2771084337 cyan red kinetics_455_0_ * k3*kenz_cplx_543_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{kenz\_cplx\_543\_0\_}$ 10 X raise oct 22 12 X raise oct 24 + conversion to k2 =4 * k3 DAG_Ca_PLA2_p_545_0_ APC_550_0_ kenz_cplx_548_0_ kenz_547_0_ 1 205.882352941 19.2771084337 pink red kinetics_455_0_ * ( k1 * DAG_Ca_PLA2_p_545_0_*APC_550_0_ - k2 * kenz_cplx_548_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{DAG\_Ca\_PLA2\_p\_545\_0\_}\mathrm{APC\_550\_0\_}-\mathrm{k2}\mathrm{kenz\_cplx\_548\_0\_})$ kenz_cplx_548_0_ DAG_Ca_PLA2_p_545_0_ Arachidonic_Acid_573_0_ kenz_547_0_ 2 205.882352941 19.2771084337 pink red kinetics_455_0_ * k3*kenz_cplx_548_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{kenz\_cplx\_548\_0\_}$ This form should be 3 to 6 times as fast as the Ca-only form. I have scaled by 4x which seems to give a 5x rise. 10x raise Oct 22 12 x oct 24, changed k2 = 4 * k3 PLA2_p_Ca_552_0_ APC_550_0_ kenz_cplx_555_0_ kenz_554_0_ 1 235.294117647 19.2771084337 orange red kinetics_455_0_ * ( k1 * PLA2_p_Ca_552_0_*APC_550_0_ - k2 * kenz_cplx_555_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PLA2\_p\_Ca\_552\_0\_}\mathrm{APC\_550\_0\_}-\mathrm{k2}\mathrm{kenz\_cplx\_555\_0\_})$ kenz_cplx_555_0_ PLA2_p_Ca_552_0_ Arachidonic_Acid_573_0_ kenz_554_0_ 2 235.294117647 19.2771084337 orange red kinetics_455_0_ * k3*kenz_cplx_555_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{kenz\_cplx\_555\_0\_}$ From Sternweis et al Phil Trans R Soc Lond 1992, also matched by Homma et al. k1 = 1.5e-5, now 4.2e-6 k2 = 70/sec; now 40/sec k3 = 17.5/sec; now 10/sec Note that the wording in Sternweis et al is ambiguous re the Km. PLC_Ca_581_0_ PIP2_613_0_ PLC_Ca_cplx_584_0_ PLC_Ca_583_0_ 1 323.529411765 19.2771084337 cyan red kinetics_455_0_ * ( k1 * PLC_Ca_581_0_*PIP2_613_0_ - k2 * PLC_Ca_cplx_584_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PLC\_Ca\_581\_0\_}\mathrm{PIP2\_613\_0\_}-\mathrm{k2}\mathrm{PLC\_Ca\_cplx\_584\_0\_})$ PLC_Ca_cplx_584_0_ PLC_Ca_581_0_ DAG_609_0_ IP3_611_0_ PLC_Ca_583_0_ 2 323.529411765 19.2771084337 cyan red kinetics_455_0_ * k3*PLC_Ca_cplx_584_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PLC\_Ca\_cplx\_584\_0\_}$ From Sternweis et al, Phil Trans R Soc Lond 1992, and the values from other refs eg Homma et al JBC 263(14) pp6592 1988 match. k1 = 5e-5/sec k2 = 240/sec; now 120/sec k3 = 60/sec; now 30/sec Note that the wording in Sternweis et al is ambiguous wr. to the Km for Gq vs non-Gq states of PLC. K1 is still a bit too low. Raise to 7e-5 9 Jun 1996: k1 was 0.0002, changed to 5e-5 PLC_Ca_Gq_586_0_ PIP2_613_0_ PLCb_Ca_Gq_cplx_589_0_ PLCb_Ca_Gq_588_0_ 1 338.235294118 19.2771084337 cyan red kinetics_455_0_ * ( k1 * PLC_Ca_Gq_586_0_*PIP2_613_0_ - k2 * PLCb_Ca_Gq_cplx_589_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PLC\_Ca\_Gq\_586\_0\_}\mathrm{PIP2\_613\_0\_}-\mathrm{k2}\mathrm{PLCb\_Ca\_Gq\_cplx\_589\_0\_})$ PLCb_Ca_Gq_cplx_589_0_ PLC_Ca_Gq_586_0_ DAG_609_0_ IP3_611_0_ PLCb_Ca_Gq_588_0_ 2 338.235294118 19.2771084337 cyan red kinetics_455_0_ * k3*PLCb_Ca_Gq_cplx_589_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PLCb\_Ca\_Gq\_cplx\_589\_0\_}$ Km = 25uM @ 50 uM ATP and 1mg/ml MBP (huge XS of substrate) Vmax = 4124 pmol/min/ml at a conc of 125 pmol/ml of enz, so: k3 = .5/sec (rate limiting) k1 = (k2 + k3)/Km = (.5 + 0)/(25*6e5) = 2e-8 (#/cell)^-1 #s from Sanghera et al JBC 265 pp 52 , 1990. From Nemenoff et al JBC 268(3):1960-1964 - using Sanghera's 1e-4 ratio of MAPK to protein, we get k3 = 7/sec from 1000 pmol/min/mg fig 5 MAPK_p_p_625_0_ PLA2_cytosolic_528_0_ MAPK_p_p_cplx_628_0_ MAPK_p_p_627_0_ 1 588.235294118 19.2771084337 orange red kinetics_455_0_ * ( k1 * PLA2_cytosolic_528_0_*MAPK_p_p_625_0_ - k2 * MAPK_p_p_cplx_628_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PLA2\_cytosolic\_528\_0\_}\mathrm{MAPK\_p\_p\_625\_0\_}-\mathrm{k2}\mathrm{MAPK\_p\_p\_cplx\_628\_0\_})$ MAPK_p_p_cplx_628_0_ MAPK_p_p_625_0_ PLA2_p_557_0_ MAPK_p_p_627_0_ 2 588.235294118 19.2771084337 orange red kinetics_455_0_ * k3*MAPK_p_p_cplx_628_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPK\_p\_p\_cplx\_628\_0\_}$ Ueki et al JBC 269(22):15756-15761 show the presence of this step, but not the rate consts, which are derived from Sanghera et al JBC 265(1):52-57, 1990, see the deriv in the MAPK* notes. MAPK_p_p_625_0_ craf_1_p_647_0_ MAPK_p_p_feedback_cplx_631_0_ MAPK_p_p_feedback_630_0_ 1 588.235294118 28.9156626506 orange red kinetics_455_0_ * ( k1 * MAPK_p_p_625_0_*craf_1_p_647_0_ - k2 * MAPK_p_p_feedback_cplx_631_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_p\_625\_0\_}\mathrm{craf\_1\_p\_647\_0\_}-\mathrm{k2}\mathrm{MAPK\_p\_p\_feedback\_cplx\_631\_0\_})$ MAPK_p_p_feedback_cplx_631_0_ MAPK_p_p_625_0_ craf_1_p_p_659_0_ MAPK_p_p_feedback_630_0_ 2 588.235294118 28.9156626506 orange red kinetics_455_0_ * k3*MAPK_p_p_feedback_cplx_631_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPK\_p\_p\_feedback\_cplx\_631\_0\_}$ See Porfiri and McCormick JBC 271:10 pp5871 1996 for the existence of this step. We'll take the rates from the ones used for the phosph of Raf by MAPK. Sep 17 1997: The transient activation curve matches better with k1 up by 10 x. MAPK_p_p_625_0_ Sos_773_0_ phosph_Sos_cplx_634_0_ phosph_Sos_633_0_ 1 588.235294118 38.5542168675 orange red kinetics_455_0_ * ( k1 * MAPK_p_p_625_0_*Sos_773_0_ - k2 * phosph_Sos_cplx_634_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_p\_625\_0\_}\mathrm{Sos\_773\_0\_}-\mathrm{k2}\mathrm{phosph\_Sos\_cplx\_634\_0\_})$ phosph_Sos_cplx_634_0_ MAPK_p_p_625_0_ Sos_p_771_0_ phosph_Sos_633_0_ 2 588.235294118 38.5542168675 orange red kinetics_455_0_ * k3*phosph_Sos_cplx_634_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{phosph\_Sos\_cplx\_634\_0\_}$ MAPK_p_p_625_0_ S6K_1306_0_ cluster_phospho_S6K_cplx_637_0_ cluster_phospho_S6K_636_0_ 1 588.235294118 48.1927710843 red red kinetics_455_0_ * ( k1 * MAPK_p_p_625_0_*S6K_1306_0_ - k2 * cluster_phospho_S6K_cplx_637_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_p\_625\_0\_}\mathrm{S6K\_1306\_0\_}-\mathrm{k2}\mathrm{cluster\_phospho\_S6K\_cplx\_637\_0\_})$ cluster_phospho_S6K_cplx_637_0_ MAPK_p_p_625_0_ S6K_p_1304_0_ cluster_phospho_S6K_636_0_ 2 588.235294118 48.1927710843 red red kinetics_455_0_ * k3*cluster_phospho_S6K_cplx_637_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{cluster\_phospho\_S6K\_cplx\_637\_0\_}$ MAPK_p_p_625_0_ _4E_BP_t37_46_1342_0_ MAPK_4E_BP_p_p_cplx_640_0_ MAPK_4E_BP_p_p_639_0_ 1 588.235294118 57.8313253012 red orange kinetics_455_0_ * ( k1 * MAPK_p_p_625_0_*_4E_BP_t37_46_1342_0_ - k2 * MAPK_4E_BP_p_p_cplx_640_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_p\_625\_0\_}\mathrm{\_4E\_BP\_t37\_46\_1342\_0\_}-\mathrm{k2}\mathrm{MAPK\_4E\_BP\_p\_p\_cplx\_640\_0\_})$ MAPK_4E_BP_p_p_cplx_640_0_ MAPK_p_p_625_0_ _4E_BP_t37_46_s65_1334_0_ MAPK_4E_BP_p_p_639_0_ 2 588.235294118 57.8313253012 red orange kinetics_455_0_ * k3*MAPK_4E_BP_p_p_cplx_640_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPK\_4E\_BP\_p\_p\_cplx\_640\_0\_}$ MAPK_p_p_625_0_ eIF4E_BP_thr37_46_1338_0_ MAPK_4E_BP_phospho_cplx_643_0_ MAPK_4E_BP_phospho_642_0_ 1 588.235294118 67.4698795181 red 47 kinetics_455_0_ * ( k1 * MAPK_p_p_625_0_*eIF4E_BP_thr37_46_1338_0_ - k2 * MAPK_4E_BP_phospho_cplx_643_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_p\_625\_0\_}\mathrm{eIF4E\_BP\_thr37\_46\_1338\_0\_}-\mathrm{k2}\mathrm{MAPK\_4E\_BP\_phospho\_cplx\_643\_0\_})$ MAPK_4E_BP_phospho_cplx_643_0_ MAPK_p_p_625_0_ eIF4E_BP_t37_46_s65_1340_0_ MAPK_4E_BP_phospho_642_0_ 2 588.235294118 67.4698795181 red 47 kinetics_455_0_ * k3*MAPK_4E_BP_phospho_cplx_643_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPK\_4E\_BP\_phospho\_cplx\_643\_0\_}$ craf_1_p_647_0_ MAPKK_655_0_ MEK_phospho_cplx_650_0_ MEK_phospho_649_0_ 1 617.647058824 19.2771084337 0 black kinetics_455_0_ * ( k1 * MAPKK_655_0_*craf_1_p_647_0_ - k2 * MEK_phospho_cplx_650_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPKK\_655\_0\_}\mathrm{craf\_1\_p\_647\_0\_}-\mathrm{k2}\mathrm{MEK\_phospho\_cplx\_650\_0\_})$ MEK_phospho_cplx_650_0_ craf_1_p_647_0_ MAPKK_p_671_0_ MEK_phospho_649_0_ 2 617.647058824 19.2771084337 0 black kinetics_455_0_ * k3*MEK_phospho_cplx_650_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MEK\_phospho\_cplx\_650\_0\_}$ craf_1_p_647_0_ MAPKK_p_671_0_ MEKp_phospho_cplx_653_0_ MEKp_phospho_652_0_ 1 617.647058824 28.9156626506 63 black kinetics_455_0_ * ( k1 * MAPKK_p_671_0_*craf_1_p_647_0_ - k2 * MEKp_phospho_cplx_653_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPKK\_p\_671\_0\_}\mathrm{craf\_1\_p\_647\_0\_}-\mathrm{k2}\mathrm{MEKp\_phospho\_cplx\_653\_0\_})$ MEKp_phospho_cplx_653_0_ craf_1_p_647_0_ MAPKK_p_p_663_0_ MEKp_phospho_652_0_ 2 617.647058824 28.9156626506 63 black kinetics_455_0_ * k3*MEKp_phospho_cplx_653_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MEKp\_phospho\_cplx\_653\_0\_}$ The actual MAPKK is 2 forms from Seger et al JBC 267:20 14373(1992) Vmax = 150nmol/min/mg From Haystead et al FEBS 306(1):17-22 we get Km=46.6nM for at least one of the phosphs. Putting these together: k3=0.15/sec, scale to get k2=0.6. k1=0.75/46.6nM=2.7e-5 MAPKK_p_p_663_0_ MAPK_657_0_ MAPKKtyr_cplx_666_0_ MAPKKtyr_665_0_ 1 691.176470588 19.2771084337 pink red kinetics_455_0_ * ( k1 * MAPK_657_0_*MAPKK_p_p_663_0_ - k2 * MAPKKtyr_cplx_666_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_657\_0\_}\mathrm{MAPKK\_p\_p\_663\_0\_}-\mathrm{k2}\mathrm{MAPKKtyr\_cplx\_666\_0\_})$ MAPKKtyr_cplx_666_0_ MAPKK_p_p_663_0_ MAPK_p_661_0_ MAPKKtyr_665_0_ 2 691.176470588 19.2771084337 pink red kinetics_455_0_ * k3*MAPKKtyr_cplx_666_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPKKtyr\_cplx\_666\_0\_}$ Rate consts same as for MAPKKtyr. MAPKK_p_p_663_0_ MAPK_p_661_0_ MAPKKthr_cplx_669_0_ MAPKKthr_668_0_ 1 691.176470588 28.9156626506 pink red kinetics_455_0_ * ( k1 * MAPK_p_661_0_*MAPKK_p_p_663_0_ - k2 * MAPKKthr_cplx_669_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_661\_0\_}\mathrm{MAPKK\_p\_p\_663\_0\_}-\mathrm{k2}\mathrm{MAPKKthr\_cplx\_669\_0\_})$ MAPKKthr_cplx_669_0_ MAPKK_p_p_663_0_ MAPK_p_p_625_0_ MAPKKthr_668_0_ 2 691.176470588 28.9156626506 pink red kinetics_455_0_ * k3*MAPKKthr_cplx_669_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPKKthr\_cplx\_669\_0\_}$ Kinetics are the same as for the craf-1* activity, ie., k1=1.1e-6, k2=.42, k3 =0.105 These are based on Force et al PNAS USA 91 1270-1274 1994. These parms cannot reach the observed 4X stim of MAPK. So lets increase the affinity, ie, raise k1 10X to 1.1e-5 Lets take it back down to where it was. Back up to 5X: 5.5e-6 Raf_p_GTP_Ras_673_0_ MAPKK_655_0_ Raf_p_GTP_Ras_dot_1_cplx_676_0_ Raf_p_GTP_Ras_dot_1_675_0_ 1 595.588235294 125.301204819 red red kinetics_455_0_ * ( k1 * Raf_p_GTP_Ras_673_0_*MAPKK_655_0_ - k2 * Raf_p_GTP_Ras_dot_1_cplx_676_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Raf\_p\_GTP\_Ras\_673\_0\_}\mathrm{MAPKK\_655\_0\_}-\mathrm{k2}\mathrm{Raf\_p\_GTP\_Ras\_dot\_1\_cplx\_676\_0\_})$ Raf_p_GTP_Ras_dot_1_cplx_676_0_ Raf_p_GTP_Ras_673_0_ MAPKK_p_671_0_ Raf_p_GTP_Ras_dot_1_675_0_ 2 595.588235294 125.301204819 red red kinetics_455_0_ * k3*Raf_p_GTP_Ras_dot_1_cplx_676_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Raf\_p\_GTP\_Ras\_dot\_1\_cplx\_676\_0\_}$ Same kinetics as other c-raf activated forms. See Force et al PNAS 91 1270-1274 1994. k1 = 1.1e-6, k2 = .42, k3 = 1.05 raise k1 to 5.5e-6 Raf_p_GTP_Ras_673_0_ MAPKK_p_671_0_ Raf_p_GTP_Ras_dot_2_cplx_679_0_ Raf_p_GTP_Ras_dot_2_678_0_ 1 595.588235294 115.662650602 red red kinetics_455_0_ * ( k1 * Raf_p_GTP_Ras_673_0_*MAPKK_p_671_0_ - k2 * Raf_p_GTP_Ras_dot_2_cplx_679_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Raf\_p\_GTP\_Ras\_673\_0\_}\mathrm{MAPKK\_p\_671\_0\_}-\mathrm{k2}\mathrm{Raf\_p\_GTP\_Ras\_dot\_2\_cplx\_679\_0\_})$ Raf_p_GTP_Ras_dot_2_cplx_679_0_ Raf_p_GTP_Ras_673_0_ MAPKK_p_p_663_0_ Raf_p_GTP_Ras_dot_2_678_0_ 2 595.588235294 115.662650602 red red kinetics_455_0_ * k3*Raf_p_GTP_Ras_dot_2_cplx_679_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Raf\_p\_GTP\_Ras\_dot\_2\_cplx\_679\_0\_}$ Kinetics based on the activation of Gq by the receptor complex in the Gq model (in turn based on the Mahama and Linderman model) k1 = 2e-5, k2 = 1e-10, k3 = 10 (I do not know why they even bother with k2). Lets put k1 at 2e-6 to get a reasonable equilibrium More specific values from, eg.g: Orita et al JBC 268(34) 25542-25546 from rasGRF and smgGDS: k1=3.3e-7; k2 = 0.08, k3 = 0.02 GEF_Gprot_bg_687_0_ GDP_Ras_704_0_ GEF_bg_act_Ras_cplx_690_0_ GEF_bg_act_Ras_689_0_ 1 735.294117647 19.2771084337 hotpink red kinetics_455_0_ * ( k1 * GDP_Ras_704_0_*GEF_Gprot_bg_687_0_ - k2 * GEF_bg_act_Ras_cplx_690_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GDP\_Ras\_704\_0\_}\mathrm{GEF\_Gprot\_bg\_687\_0\_}-\mathrm{k2}\mathrm{GEF\_bg\_act\_Ras\_cplx\_690\_0\_})$ GEF_bg_act_Ras_cplx_690_0_ GEF_Gprot_bg_687_0_ GTP_Ras_702_0_ GEF_bg_act_Ras_689_0_ 2 735.294117647 19.2771084337 hotpink red kinetics_455_0_ * k3*GEF_bg_act_Ras_cplx_690_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{GEF\_bg\_act\_Ras\_cplx\_690\_0\_}$ inact_GEF_692_0_ GDP_Ras_704_0_ basal_GEF_activity_cplx_695_0_ basal_GEF_activity_694_0_ 1 750.0 19.2771084337 red hotpink kinetics_455_0_ * ( k1 * GDP_Ras_704_0_*inact_GEF_692_0_ - k2 * basal_GEF_activity_cplx_695_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GDP\_Ras\_704\_0\_}\mathrm{inact\_GEF\_692\_0\_}-\mathrm{k2}\mathrm{basal\_GEF\_activity\_cplx\_695\_0\_})$ basal_GEF_activity_cplx_695_0_ inact_GEF_692_0_ GTP_Ras_702_0_ basal_GEF_activity_694_0_ 2 750.0 19.2771084337 red hotpink kinetics_455_0_ * k3*basal_GEF_activity_cplx_695_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{basal\_GEF\_activity\_cplx\_695\_0\_}$ Kinetics same as GEF-bg-act-ras GEF_p_697_0_ GDP_Ras_704_0_ GEF_p_act_Ras_cplx_700_0_ GEF_p_act_Ras_699_0_ 1 764.705882353 19.2771084337 hotpink red kinetics_455_0_ * ( k1 * GDP_Ras_704_0_*GEF_p_697_0_ - k2 * GEF_p_act_Ras_cplx_700_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GDP\_Ras\_704\_0\_}\mathrm{GEF\_p\_697\_0\_}-\mathrm{k2}\mathrm{GEF\_p\_act\_Ras\_cplx\_700\_0\_})$ GEF_p_act_Ras_cplx_700_0_ GEF_p_697_0_ GTP_Ras_702_0_ GEF_p_act_Ras_699_0_ 2 764.705882353 19.2771084337 hotpink red kinetics_455_0_ * k3*GEF_p_act_Ras_cplx_700_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{GEF\_p\_act\_Ras\_cplx\_700\_0\_}$ From Eccleston et al JBC 268(36)pp27012-19 get Kd _lessthan_ 2uM, kcat - 10/sec From Martin et al Cell 63 843-849 1990 get Kd ~ 250 nM, kcat = 20/min I will go with the Eccleston figures as there are good error bars (10%). In general the values are reasonably close. k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting) 5 Nov 2002: Changed ratio term to 4 from 100. Now we have k1=8.25e-5; k2=40, k3=10. k3 is still rate-limiting. GAP_708_0_ GTP_Ras_702_0_ GAP_inact_Ras_cplx_711_0_ GAP_inact_Ras_710_0_ 1 823.529411765 19.2771084337 red red kinetics_455_0_ * ( k1 * GAP_708_0_*GTP_Ras_702_0_ - k2 * GAP_inact_Ras_cplx_711_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GAP\_708\_0\_}\mathrm{GTP\_Ras\_702\_0\_}-\mathrm{k2}\mathrm{GAP\_inact\_Ras\_cplx\_711\_0\_})$ GAP_inact_Ras_cplx_711_0_ GAP_708_0_ GDP_Ras_704_0_ GAP_inact_Ras_710_0_ 2 823.529411765 19.2771084337 red red kinetics_455_0_ * k3*GAP_inact_Ras_cplx_711_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{GAP\_inact\_Ras\_cplx\_711\_0\_}$ Kinetics same as GEF-bg_act-ras CaM_GEF_715_0_ GDP_Ras_704_0_ CaM_GEF_act_Ras_cplx_718_0_ CaM_GEF_act_Ras_717_0_ 1 852.941176471 19.2771084337 pink red kinetics_455_0_ * ( k1 * GDP_Ras_704_0_*CaM_GEF_715_0_ - k2 * CaM_GEF_act_Ras_cplx_718_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GDP\_Ras\_704\_0\_}\mathrm{CaM\_GEF\_715\_0\_}-\mathrm{k2}\mathrm{CaM\_GEF\_act\_Ras\_cplx\_718\_0\_})$ CaM_GEF_act_Ras_cplx_718_0_ CaM_GEF_715_0_ GTP_Ras_702_0_ CaM_GEF_act_Ras_717_0_ 2 852.941176471 19.2771084337 pink red kinetics_455_0_ * k3*CaM_GEF_act_Ras_cplx_718_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{CaM\_GEF\_act\_Ras\_cplx\_718\_0\_}$ Hsu et al JBC 266:1 603-608 1991 Km = 385 +- 100 uM, Vm = 5.1 +-1 pmol/min/ug for PLC-771. Other sites have similar range, but are not stim as much by EGF. k1 = 2.8e-2/385/6e5 = 1.2e-10. Phenomenally slow. But Sherrill and Kyte say turnover # for angiotensin II is 5/min for cell extt, and 2/min for placental. Also see Okada et al for Shc rates which are much faster. L_dot_EGFR_738_0_ Ca_dot_PLC_g_795_0_ Ca_dot_PLC_g_phospho_cplx_741_0_ Ca_dot_PLC_g_phospho_740_0_ 1 897.058823529 19.2771084337 red red kinetics_455_0_ * ( k1 * L_dot_EGFR_738_0_*Ca_dot_PLC_g_795_0_ - k2 * Ca_dot_PLC_g_phospho_cplx_741_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{L\_dot\_EGFR\_738\_0\_}\mathrm{Ca\_dot\_PLC\_g\_795\_0\_}-\mathrm{k2}\mathrm{Ca\_dot\_PLC\_g\_phospho\_cplx\_741\_0\_})$ Ca_dot_PLC_g_phospho_cplx_741_0_ L_dot_EGFR_738_0_ Ca_dot_PLC_g_p_799_0_ Ca_dot_PLC_g_phospho_740_0_ 2 897.058823529 19.2771084337 red red kinetics_455_0_ * k3*Ca_dot_PLC_g_phospho_cplx_741_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Ca\_dot\_PLC\_g\_phospho\_cplx\_741\_0\_}$ Rates from Okada et al JBC 270:35 pp 20737 1995 Km = 0.70 to 0.85 uM, Vmax = 4.4 to 5.0 pmol/min. Unfortunately the amount of enzyme is not known, the prep is only partially purified. Time course of phosph is max within 30 sec, falls back within 20 min. Ref: Sasaoka et al JBC 269:51 32621 1994. Use k3 = 0.1 based on this tau. L_dot_EGFR_738_0_ SHC_761_0_ SHC_phospho_cplx_744_0_ SHC_phospho_743_0_ 1 897.058823529 28.9156626506 red red kinetics_455_0_ * ( k1 * SHC_761_0_*L_dot_EGFR_738_0_ - k2 * SHC_phospho_cplx_744_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{SHC\_761\_0\_}\mathrm{L\_dot\_EGFR\_738\_0\_}-\mathrm{k2}\mathrm{SHC\_phospho\_cplx\_744\_0\_})$ SHC_phospho_cplx_744_0_ L_dot_EGFR_738_0_ SHC_p_763_0_ SHC_phospho_743_0_ 2 897.058823529 28.9156626506 red red kinetics_455_0_ * k3*SHC_phospho_cplx_744_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{SHC\_phospho\_cplx\_744\_0\_}$ SHC_p_dot_Sos_dot_Grb2_756_0_ GDP_Ras_704_0_ Sos_dot_Ras_GEF_cplx_759_0_ Sos_dot_Ras_GEF_758_0_ 1 0.0 212.048192771 brown red kinetics_455_0_ * ( k1 * GDP_Ras_704_0_*SHC_p_dot_Sos_dot_Grb2_756_0_ - k2 * Sos_dot_Ras_GEF_cplx_759_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GDP\_Ras\_704\_0\_}\mathrm{SHC\_p\_dot\_Sos\_dot\_Grb2\_756\_0\_}-\mathrm{k2}\mathrm{Sos\_dot\_Ras\_GEF\_cplx\_759\_0\_})$ Sos_dot_Ras_GEF_cplx_759_0_ SHC_p_dot_Sos_dot_Grb2_756_0_ GTP_Ras_702_0_ Sos_dot_Ras_GEF_758_0_ 2 0.0 212.048192771 brown red kinetics_455_0_ * k3*Sos_dot_Ras_GEF_cplx_759_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Sos\_dot\_Ras\_GEF\_cplx\_759\_0\_}$ Mainly Homma et al JBC 263:14 1988 pp 6592, but these parms are the Ca-stimulated form. It is not clear whether the enzyme is activated by tyrosine phosphorylation at this point or not. Wahl et al JBC 267:15 10447-10456 1992 say that the Ca_stim and phosph form has 7X higher affinity for substrate than control. This is close to Wahl's figure 7, which I am using as reference. 176.470588235 212.048192771 pink red kinetics_455_0_ * ( kcat * PIP2_613_0_ * Ca_dot_PLC_g_795_0_ / ( Km + PIP2_613_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{PIP2\_613\_0\_}\mathrm{Ca\_dot\_PLC\_g\_795\_0\_}}{\mathrm{Km}+\mathrm{PIP2\_613\_0\_}}$ Mainly Homma et al JBC 263:14 1988 pp 6592, but these parms are the Ca-stimulated form. It is not clear whether the enzyme is activated by tyrosine phosphorylation at this point or not. Wahl et al JBC 267:15 10447-10456 1992 say that this has 7X higher affinity for substrate than control. 191.176470588 212.048192771 pink red kinetics_455_0_ * ( kcat * PIP2_613_0_ * Ca_dot_PLC_g_p_799_0_ / ( Km + PIP2_613_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{PIP2\_613\_0\_}\mathrm{Ca\_dot\_PLC\_g\_p\_799\_0\_}}{\mathrm{Km}+\mathrm{PIP2\_613\_0\_}}$ PLCg_basal_803_0_ PLC_g_791_0_ PLC_g_phospho_cplx_806_0_ PLC_g_phospho_805_0_ 1 205.882352941 212.048192771 red 33 kinetics_455_0_ * ( k1 * PLCg_basal_803_0_*PLC_g_791_0_ - k2 * PLC_g_phospho_cplx_806_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PLCg\_basal\_803\_0\_}\mathrm{PLC\_g\_791\_0\_}-\mathrm{k2}\mathrm{PLC\_g\_phospho\_cplx\_806\_0\_})$ PLC_g_phospho_cplx_806_0_ PLCg_basal_803_0_ PLC_g_p_793_0_ PLC_g_phospho_805_0_ 2 205.882352941 212.048192771 red 33 kinetics_455_0_ * k3*PLC_g_phospho_cplx_806_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PLC\_g\_phospho\_cplx\_806\_0\_}$ Rates from autocamtide phosphorylation, from Hanson and Schulman JBC 267:24 17216-17224 1992. Jan 1 1998: Speed up 12x to match fig 5. tot_CaM_CaMKII_830_0_ CaMKII_thr286_826_0_ CaM_act_305_cplx_833_0_ CaM_act_305_832_0_ 1 316.176470588 308.43373494 green red kinetics_455_0_ * ( k1 * CaMKII_thr286_826_0_*tot_CaM_CaMKII_830_0_ - k2 * CaM_act_305_cplx_833_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_thr286\_826\_0\_}\mathrm{tot\_CaM\_CaMKII\_830\_0\_}-\mathrm{k2}\mathrm{CaM\_act\_305\_cplx\_833\_0\_})$ CaM_act_305_cplx_833_0_ tot_CaM_CaMKII_830_0_ CaMKII_p_p_p_824_0_ CaM_act_305_832_0_ 2 316.176470588 308.43373494 green red kinetics_455_0_ * k3*CaM_act_305_cplx_833_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{CaM\_act\_305\_cplx\_833\_0\_}$ tot_CaM_CaMKII_830_0_ CaMKII_CaM_820_0_ CaM_act_286_cplx_836_0_ CaM_act_286_835_0_ 1 316.176470588 318.072289157 green red kinetics_455_0_ * ( k1 * CaMKII_CaM_820_0_*tot_CaM_CaMKII_830_0_ - k2 * CaM_act_286_cplx_836_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_CaM\_820\_0\_}\mathrm{tot\_CaM\_CaMKII\_830\_0\_}-\mathrm{k2}\mathrm{CaM\_act\_286\_cplx\_836\_0\_})$ CaM_act_286_cplx_836_0_ tot_CaM_CaMKII_830_0_ CaMKII_thr286_p_CaM_822_0_ CaM_act_286_835_0_ 2 316.176470588 318.072289157 green red kinetics_455_0_ * k3*CaM_act_286_cplx_836_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{CaM\_act\_286\_cplx\_836\_0\_}$ See Hanson and Schulman again, for afterburst rates of phosph. tot_autonomous_CaMKII_838_0_ CaMKII_thr286_826_0_ auton_305_cplx_841_0_ auton_305_840_0_ 1 375.0 308.43373494 green red kinetics_455_0_ * ( k1 * CaMKII_thr286_826_0_*tot_autonomous_CaMKII_838_0_ - k2 * auton_305_cplx_841_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_thr286\_826\_0\_}\mathrm{tot\_autonomous\_CaMKII\_838\_0\_}-\mathrm{k2}\mathrm{auton\_305\_cplx\_841\_0\_})$ auton_305_cplx_841_0_ tot_autonomous_CaMKII_838_0_ CaMKII_p_p_p_824_0_ auton_305_840_0_ 2 375.0 308.43373494 green red kinetics_455_0_ * k3*auton_305_cplx_841_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{auton\_305\_cplx\_841\_0\_}$ tot_autonomous_CaMKII_838_0_ CaMKII_CaM_820_0_ auton_286_cplx_844_0_ auton_286_843_0_ 1 375.0 318.072289157 green red kinetics_455_0_ * ( k1 * CaMKII_CaM_820_0_*tot_autonomous_CaMKII_838_0_ - k2 * auton_286_cplx_844_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_CaM\_820\_0\_}\mathrm{tot\_autonomous\_CaMKII\_838\_0\_}-\mathrm{k2}\mathrm{auton\_286\_cplx\_844\_0\_})$ auton_286_cplx_844_0_ tot_autonomous_CaMKII_838_0_ CaMKII_thr286_p_CaM_822_0_ auton_286_843_0_ 2 375.0 318.072289157 green red kinetics_455_0_ * k3*auton_286_cplx_844_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{auton\_286\_cplx\_844\_0\_}$ From Seki et al ABB 316(2):673-679 CaM_bo_Ca_bc_n_CaNAB_866_0_ neurogranin_p_860_0_ dephosph_neurogranin_cplx_869_0_ dephosph_neurogranin_868_0_ 1 544.117647059 212.048192771 darkblue red kinetics_455_0_ * ( k1 * CaM_bo_Ca_bc_n_CaNAB_866_0_*neurogranin_p_860_0_ - k2 * dephosph_neurogranin_cplx_869_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaM\_bo\_Ca\_bc\_n\_CaNAB\_866\_0\_}\mathrm{neurogranin\_p\_860\_0\_}-\mathrm{k2}\mathrm{dephosph\_neurogranin\_cplx\_869\_0\_})$ dephosph_neurogranin_cplx_869_0_ CaM_bo_Ca_bc_n_CaNAB_866_0_ neurogranin_862_0_ dephosph_neurogranin_868_0_ 2 544.117647059 212.048192771 darkblue red kinetics_455_0_ * k3*dephosph_neurogranin_cplx_869_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephosph\_neurogranin\_cplx\_869\_0\_}$ CaM_bo_Ca_bc_n_CaNAB_866_0_ I1_p_921_0_ dephosph_inhib1_cplx_872_0_ dephosph_inhib1_871_0_ 1 544.117647059 221.686746988 darkblue red kinetics_455_0_ * ( k1 * I1_p_921_0_*CaM_bo_Ca_bc_n_CaNAB_866_0_ - k2 * dephosph_inhib1_cplx_872_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{I1\_p\_921\_0\_}\mathrm{CaM\_bo\_Ca\_bc\_n\_CaNAB\_866\_0\_}-\mathrm{k2}\mathrm{dephosph\_inhib1\_cplx\_872\_0\_})$ dephosph_inhib1_cplx_872_0_ CaM_bo_Ca_bc_n_CaNAB_866_0_ I1_919_0_ dephosph_inhib1_871_0_ 2 544.117647059 221.686746988 darkblue red kinetics_455_0_ * k3*dephosph_inhib1_cplx_872_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephosph\_inhib1\_cplx\_872\_0\_}$ CaM_bo_Ca_bc_n_CaNAB_866_0_ PP1_I1_p_923_0_ dephosph_PP1_I_p_cplx_875_0_ dephosph_PP1_I_p_874_0_ 1 544.117647059 231.325301205 darkblue white kinetics_455_0_ * ( k1 * CaM_bo_Ca_bc_n_CaNAB_866_0_*PP1_I1_p_923_0_ - k2 * dephosph_PP1_I_p_cplx_875_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaM\_bo\_Ca\_bc\_n\_CaNAB\_866\_0\_}\mathrm{PP1\_I1\_p\_923\_0\_}-\mathrm{k2}\mathrm{dephosph\_PP1\_I\_p\_cplx\_875\_0\_})$ dephosph_PP1_I_p_cplx_875_0_ CaM_bo_Ca_bc_n_CaNAB_866_0_ PP1_I1_925_0_ dephosph_PP1_I_p_874_0_ 2 544.117647059 231.325301205 darkblue white kinetics_455_0_ * k3*dephosph_PP1_I_p_cplx_875_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephosph\_PP1\_I\_p\_cplx\_875\_0\_}$ The rates here are so slow I do not know if we should even bother with this enz reacn. These numbers are from Liu and Storm. Other refs suggest that the Km stays the same but the Vmax goes to 10% of the CaM stim levels. Prev: k1=2.2e-9, k2 = 0.0052, k3 = 0.0013 New : k1=5.7e-8, k2=.136, k3=.034 CaNAB_Ca4_877_0_ I1_p_921_0_ dephosph_inhib1_noCaM_cplx_880_0_ dephosph_inhib1_noCaM_879_0_ 1 558.823529412 212.048192771 tan red kinetics_455_0_ * ( k1 * I1_p_921_0_*CaNAB_Ca4_877_0_ - k2 * dephosph_inhib1_noCaM_cplx_880_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{I1\_p\_921\_0\_}\mathrm{CaNAB\_Ca4\_877\_0\_}-\mathrm{k2}\mathrm{dephosph\_inhib1\_noCaM\_cplx\_880\_0\_})$ dephosph_inhib1_noCaM_cplx_880_0_ CaNAB_Ca4_877_0_ I1_919_0_ dephosph_inhib1_noCaM_879_0_ 2 558.823529412 212.048192771 tan red kinetics_455_0_ * k3*dephosph_inhib1_noCaM_cplx_880_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephosph\_inhib1\_noCaM\_cplx\_880\_0\_}$ The rates are from Stralfors et al Eur J Biochem 149 295-303 giving Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14. Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so k1 becomes 5.72e-6 Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10 to 5.72e-7, 1.4, 0.35 PP1_active_902_0_ CaMKII_thr286_p_CaM_822_0_ Deph_thr286_cplx_905_0_ Deph_thr286_904_0_ 1 588.235294118 212.048192771 cyan red kinetics_455_0_ * ( k1 * CaMKII_thr286_p_CaM_822_0_*PP1_active_902_0_ - k2 * Deph_thr286_cplx_905_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_thr286\_p\_CaM\_822\_0\_}\mathrm{PP1\_active\_902\_0\_}-\mathrm{k2}\mathrm{Deph\_thr286\_cplx\_905\_0\_})$ Deph_thr286_cplx_905_0_ PP1_active_902_0_ CaMKII_CaM_820_0_ Deph_thr286_904_0_ 2 588.235294118 212.048192771 cyan red kinetics_455_0_ * k3*Deph_thr286_cplx_905_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Deph\_thr286\_cplx\_905\_0\_}$ PP1_active_902_0_ CaMKII_p_p_p_824_0_ Deph_thr305_cplx_908_0_ Deph_thr305_907_0_ 1 588.235294118 221.686746988 cyan red kinetics_455_0_ * ( k1 * CaMKII_p_p_p_824_0_*PP1_active_902_0_ - k2 * Deph_thr305_cplx_908_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_p\_p\_p\_824\_0\_}\mathrm{PP1\_active\_902\_0\_}-\mathrm{k2}\mathrm{Deph\_thr305\_cplx\_908\_0\_})$ Deph_thr305_cplx_908_0_ PP1_active_902_0_ CaMKII_thr286_826_0_ Deph_thr305_907_0_ 2 588.235294118 221.686746988 cyan red kinetics_455_0_ * k3*Deph_thr305_cplx_908_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Deph\_thr305\_cplx\_908\_0\_}$ See Cohen et al PP1_active_902_0_ CaMKII_thr306_828_0_ Deph_thr306_cplx_911_0_ Deph_thr306_910_0_ 1 588.235294118 231.325301205 cyan red kinetics_455_0_ * ( k1 * CaMKII_thr306_828_0_*PP1_active_902_0_ - k2 * Deph_thr306_cplx_911_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_thr306\_828\_0\_}\mathrm{PP1\_active\_902\_0\_}-\mathrm{k2}\mathrm{Deph\_thr306\_cplx\_911\_0\_})$ Deph_thr306_cplx_911_0_ PP1_active_902_0_ CaMKII_818_0_ Deph_thr306_910_0_ 2 588.235294118 231.325301205 cyan red kinetics_455_0_ * k3*Deph_thr306_cplx_911_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Deph\_thr306\_cplx\_911\_0\_}$ PP1_active_902_0_ CaMKII_p_p_p_824_0_ Deph_thr286c_cplx_914_0_ Deph_thr286c_913_0_ 1 588.235294118 240.963855422 cyan red kinetics_455_0_ * ( k1 * CaMKII_p_p_p_824_0_*PP1_active_902_0_ - k2 * Deph_thr286c_cplx_914_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_p\_p\_p\_824\_0\_}\mathrm{PP1\_active\_902\_0\_}-\mathrm{k2}\mathrm{Deph\_thr286c\_cplx\_914\_0\_})$ Deph_thr286c_cplx_914_0_ PP1_active_902_0_ CaMKII_thr306_828_0_ Deph_thr286c_913_0_ 2 588.235294118 240.963855422 cyan red kinetics_455_0_ * k3*Deph_thr286c_cplx_914_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Deph\_thr286c\_cplx\_914\_0\_}$ PP1_active_902_0_ CaMKII_thr286_826_0_ Deph_thr286b_cplx_917_0_ Deph_thr286b_916_0_ 1 588.235294118 250.602409639 cyan red kinetics_455_0_ * ( k1 * CaMKII_thr286_826_0_*PP1_active_902_0_ - k2 * Deph_thr286b_cplx_917_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKII\_thr286\_826\_0\_}\mathrm{PP1\_active\_902\_0\_}-\mathrm{k2}\mathrm{Deph\_thr286b\_cplx\_917\_0\_})$ Deph_thr286b_cplx_917_0_ PP1_active_902_0_ CaMKII_818_0_ Deph_thr286b_916_0_ 2 588.235294118 250.602409639 cyan red kinetics_455_0_ * k3*Deph_thr286b_cplx_917_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Deph\_thr286b\_cplx\_917\_0\_}$ This pathway inhibits Ras when cAMP is elevated. See: Hordijk et al JBC 269:5 3534-3538 1994 Burgering et al EMBO J 12:11 4211-4220 1993 The rates are the same as used in PKA-phosph-I1 PKA_active_955_0_ inact_GEF_692_0_ PKA_phosph_GEF_cplx_958_0_ PKA_phosph_GEF_957_0_ 1 882.352941176 212.048192771 yellow red kinetics_455_0_ * ( k1 * PKA_active_955_0_*inact_GEF_692_0_ - k2 * PKA_phosph_GEF_cplx_958_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PKA\_active\_955\_0\_}\mathrm{inact\_GEF\_692\_0\_}-\mathrm{k2}\mathrm{PKA\_phosph\_GEF\_cplx\_958\_0\_})$ PKA_phosph_GEF_cplx_958_0_ PKA_active_955_0_ inact_GEF_p_713_0_ PKA_phosph_GEF_957_0_ 2 882.352941176 212.048192771 yellow red kinetics_455_0_ * k3*PKA_phosph_GEF_cplx_958_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKA\_phosph\_GEF\_cplx\_958\_0\_}$ #s from Bramson et al CRC crit rev Biochem 15:2 93-124. They have a huge list of peptide substrates and I have chosen high-ish rates. These consts give too much PKA activity, so lower Vmax 1/3. Now, k1 = 3e-5, k2 = 36, k3 = 9 (still pretty fast). Also lower Km 1/3 so k1 = 1e-5 Cohen et al FEBS Lett 76:182-86 1977 say rate =30% PKA act on phosphokinase beta. PKA_active_955_0_ I1_919_0_ PKA_phosph_I1_cplx_961_0_ PKA_phosph_I1_960_0_ 1 882.352941176 221.686746988 yellow red kinetics_455_0_ * ( k1 * PKA_active_955_0_*I1_919_0_ - k2 * PKA_phosph_I1_cplx_961_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PKA\_active\_955\_0\_}\mathrm{I1\_919\_0\_}-\mathrm{k2}\mathrm{PKA\_phosph\_I1\_cplx\_961\_0\_})$ PKA_phosph_I1_cplx_961_0_ PKA_active_955_0_ I1_p_921_0_ PKA_phosph_I1_960_0_ 2 882.352941176 221.686746988 yellow red kinetics_455_0_ * k3*PKA_phosph_I1_cplx_961_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PKA\_phosph\_I1\_cplx\_961\_0\_}$ Same rates as PKA-phosph-I1 PKA_active_955_0_ cAMP_PDE_1028_0_ phosph_PDE_cplx_964_0_ phosph_PDE_963_0_ 1 882.352941176 231.325301205 yellow red kinetics_455_0_ * ( k1 * PKA_active_955_0_*cAMP_PDE_1028_0_ - k2 * phosph_PDE_cplx_964_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PKA\_active\_955\_0\_}\mathrm{cAMP\_PDE\_1028\_0\_}-\mathrm{k2}\mathrm{phosph\_PDE\_cplx\_964\_0\_})$ phosph_PDE_cplx_964_0_ PKA_active_955_0_ cAMP_PDE_p_1033_0_ phosph_PDE_963_0_ 2 882.352941176 231.325301205 yellow red kinetics_455_0_ * k3*phosph_PDE_cplx_964_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{phosph\_PDE\_cplx\_964\_0\_}$ 29.4117647059 404.819277108 orange red kinetics_455_0_ * ( kcat * ATP_1002_0_ * AC1_CaM_1004_0_ / ( Km + ATP_1002_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{ATP\_1002\_0\_}\mathrm{AC1\_CaM\_1004\_0\_}}{\mathrm{Km}+\mathrm{ATP\_1002\_0\_}}$ Reduced Km to match expt data for basal activation of AC2 by PKC. Now k1 = 2.9e-6, k2 = 72, k3 = 18 58.8235294118 404.819277108 yellow red kinetics_455_0_ * ( kcat * ATP_1002_0_ * AC2_p_1010_0_ / ( Km + ATP_1002_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{ATP\_1002\_0\_}\mathrm{AC2\_p\_1010\_0\_}}{\mathrm{Km}+\mathrm{ATP\_1002\_0\_}}$ 73.5294117647 404.819277108 yellow red kinetics_455_0_ * ( kcat * ATP_1002_0_ * AC2_Gs_1014_0_ / ( Km + ATP_1002_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{ATP\_1002\_0\_}\mathrm{AC2\_Gs\_1014\_0\_}}{\mathrm{Km}+\mathrm{ATP\_1002\_0\_}}$ 102.941176471 404.819277108 orange red kinetics_455_0_ * ( kcat * ATP_1002_0_ * AC1_Gs_1020_0_ / ( Km + ATP_1002_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{ATP\_1002\_0\_}\mathrm{AC1\_Gs\_1020\_0\_}}{\mathrm{Km}+\mathrm{ATP\_1002\_0\_}}$ 117.647058824 404.819277108 green red kinetics_455_0_ * ( kcat * ATP_1002_0_ * AC2_p_Gs_1024_0_ / ( Km + ATP_1002_0_)) $\mathrm{kinetics\_455\_0\_}\frac{\mathrm{kcat}\mathrm{ATP\_1002\_0\_}\mathrm{AC2\_p\_Gs\_1024\_0\_}}{\mathrm{Km}+\mathrm{ATP\_1002\_0\_}}$ Best rates are from Conti et al Biochem 34 7979-7987 1995. Though these are for the Sertoli cell form, it looks like they carry nicely into alternatively spliced brain form. See Sette et al JBC 269:28 18271-18274 Km ~2 uM, Vmax est ~ 10 umol/min/mg for pure form. Brain protein is 93 kD but this was 67. So k3 ~10, k2 ~40, k1 ~4.2e-6 cAMP_PDE_1028_0_ cAMP_1000_0_ PDE_cplx_1031_0_ PDE_1030_0_ 1 7.35294117647 510.843373494 green red kinetics_455_0_ * ( k1 * cAMP_1000_0_*cAMP_PDE_1028_0_ - k2 * PDE_cplx_1031_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{cAMP\_1000\_0\_}\mathrm{cAMP\_PDE\_1028\_0\_}-\mathrm{k2}\mathrm{PDE\_cplx\_1031\_0\_})$ PDE_cplx_1031_0_ cAMP_PDE_1028_0_ AMP_1062_0_ PDE_1030_0_ 2 7.35294117647 510.843373494 green red kinetics_455_0_ * k3*PDE_cplx_1031_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PDE\_cplx\_1031\_0\_}$ This form has about twice the activity of the unphosphorylated form. See Sette et al JBC 269:28 18271-18274 1994. We'll ignore cGMP effects for now. cAMP_PDE_p_1033_0_ cAMP_1000_0_ PDE_p_cplx_1036_0_ PDE_p_1035_0_ 1 22.0588235294 510.843373494 green red kinetics_455_0_ * ( k1 * cAMP_1000_0_*cAMP_PDE_p_1033_0_ - k2 * PDE_p_cplx_1036_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{cAMP\_1000\_0\_}\mathrm{cAMP\_PDE\_p\_1033\_0\_}-\mathrm{k2}\mathrm{PDE\_p\_cplx\_1036\_0\_})$ PDE_p_cplx_1036_0_ cAMP_PDE_p_1033_0_ AMP_1062_0_ PDE_p_1035_0_ 2 22.0588235294 510.843373494 green red kinetics_455_0_ * k3*PDE_p_cplx_1036_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PDE\_p\_cplx\_1036\_0\_}$ Rate is 1/6 of the CaM stim form. We'll just reduce all lf k1, k2, k3 so that the Vmax goes down 1/6. PDE1_1038_0_ cAMP_1000_0_ PDE1_cplx_1041_0_ PDE1_1040_0_ 1 36.7647058824 510.843373494 green red kinetics_455_0_ * ( k1 * cAMP_1000_0_*PDE1_1038_0_ - k2 * PDE1_cplx_1041_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{cAMP\_1000\_0\_}\mathrm{PDE1\_1038\_0\_}-\mathrm{k2}\mathrm{PDE1\_cplx\_1041\_0\_})$ PDE1_cplx_1041_0_ PDE1_1038_0_ AMP_1062_0_ PDE1_1040_0_ 2 36.7647058824 510.843373494 green red kinetics_455_0_ * k3*PDE1_cplx_1041_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PDE1\_cplx\_1041\_0\_}$ Max activity ~10umol/min/mg in presence of lots of CaM. Affinity is low, 40 uM. k3 = 10, k2 = 40, k1 = (50/40) / 6e5. CaM_dot_PDE1_1043_0_ cAMP_1000_0_ CaM_dot_PDE1_cplx_1046_0_ CaM_dot_PDE1_1045_0_ 1 51.4705882353 510.843373494 green red kinetics_455_0_ * ( k1 * cAMP_1000_0_*CaM_dot_PDE1_1043_0_ - k2 * CaM_dot_PDE1_cplx_1046_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{cAMP\_1000\_0\_}\mathrm{CaM\_dot\_PDE1\_1043\_0\_}-\mathrm{k2}\mathrm{CaM\_dot\_PDE1\_cplx\_1046\_0\_})$ CaM_dot_PDE1_cplx_1046_0_ CaM_dot_PDE1_1043_0_ AMP_1062_0_ CaM_dot_PDE1_1045_0_ 2 51.4705882353 510.843373494 green red kinetics_455_0_ * k3*CaM_dot_PDE1_cplx_1046_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{CaM\_dot\_PDE1\_cplx\_1046\_0\_}$ The original kinetics have been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. As noted in the NOTES, the only constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. It would be nice to have more accurate estimates of rate consts and MKP-1 levels from the literature. Effective Km : 67 nM kcat = 1.43 umol/min/mg MKP_1_1106_0_ MAPK_p_661_0_ MKP1_tyr_deph_cplx_1109_0_ MKP1_tyr_deph_1108_0_ 1 441.176470588 404.819277108 hotpink red kinetics_455_0_ * ( k1 * MKP_1_1106_0_*MAPK_p_661_0_ - k2 * MKP1_tyr_deph_cplx_1109_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MKP\_1\_1106\_0\_}\mathrm{MAPK\_p\_661\_0\_}-\mathrm{k2}\mathrm{MKP1\_tyr\_deph\_cplx\_1109\_0\_})$ MKP1_tyr_deph_cplx_1109_0_ MKP_1_1106_0_ MAPK_657_0_ MKP1_tyr_deph_1108_0_ 2 441.176470588 404.819277108 hotpink red kinetics_455_0_ * k3*MKP1_tyr_deph_cplx_1109_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MKP1\_tyr\_deph\_cplx\_1109\_0\_}$ See MKP1-tyr-deph MKP_1_1106_0_ MAPK_p_p_625_0_ MKP1_thr_deph_cplx_1112_0_ MKP1_thr_deph_1111_0_ 1 441.176470588 414.457831325 hotpink red kinetics_455_0_ * ( k1 * MAPK_p_p_625_0_*MKP_1_1106_0_ - k2 * MKP1_thr_deph_cplx_1112_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{MAPK\_p\_p\_625\_0\_}\mathrm{MKP\_1\_1106\_0\_}-\mathrm{k2}\mathrm{MKP1\_thr\_deph\_cplx\_1112\_0\_})$ MKP1_thr_deph_cplx_1112_0_ MKP_1_1106_0_ MAPK_p_661_0_ MKP1_thr_deph_1111_0_ 2 441.176470588 414.457831325 hotpink red kinetics_455_0_ * k3*MKP1_thr_deph_cplx_1112_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MKP1\_thr\_deph\_cplx\_1112\_0\_}$ See parent PPhosphatase2A for parms PPhosphatase2A_1114_0_ craf_1_p_647_0_ craf_dephospho_cplx_1117_0_ craf_dephospho_1116_0_ 1 455.882352941 404.819277108 hotpink red kinetics_455_0_ * ( k1 * PPhosphatase2A_1114_0_*craf_1_p_647_0_ - k2 * craf_dephospho_cplx_1117_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PPhosphatase2A\_1114\_0\_}\mathrm{craf\_1\_p\_647\_0\_}-\mathrm{k2}\mathrm{craf\_dephospho\_cplx\_1117\_0\_})$ craf_dephospho_cplx_1117_0_ PPhosphatase2A_1114_0_ craf_1_645_0_ craf_dephospho_1116_0_ 2 455.882352941 404.819277108 hotpink red kinetics_455_0_ * k3*craf_dephospho_cplx_1117_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{craf\_dephospho\_cplx\_1117\_0\_}$ See: Kyriakis et al Nature 358 pp 417-421 1992 Ahn et al Curr Op Cell Biol 4:992-999 1992 for this pathway. See parent PPhosphatase2A for parms. PPhosphatase2A_1114_0_ MAPKK_p_p_663_0_ MAPKK_dephospho_cplx_1120_0_ MAPKK_dephospho_1119_0_ 1 455.882352941 414.457831325 hotpink red kinetics_455_0_ * ( k1 * PPhosphatase2A_1114_0_*MAPKK_p_p_663_0_ - k2 * MAPKK_dephospho_cplx_1120_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PPhosphatase2A\_1114\_0\_}\mathrm{MAPKK\_p\_p\_663\_0\_}-\mathrm{k2}\mathrm{MAPKK\_dephospho\_cplx\_1120\_0\_})$ MAPKK_dephospho_cplx_1120_0_ PPhosphatase2A_1114_0_ MAPKK_p_671_0_ MAPKK_dephospho_1119_0_ 2 455.882352941 414.457831325 hotpink red kinetics_455_0_ * k3*MAPKK_dephospho_cplx_1120_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPKK\_dephospho\_cplx\_1120\_0\_}$ PPhosphatase2A_1114_0_ MAPKK_p_671_0_ MAPKK_dephospho_ser_cplx_1123_0_ MAPKK_dephospho_ser_1122_0_ 1 455.882352941 424.096385542 hotpink red kinetics_455_0_ * ( k1 * PPhosphatase2A_1114_0_*MAPKK_p_671_0_ - k2 * MAPKK_dephospho_ser_cplx_1123_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PPhosphatase2A\_1114\_0\_}\mathrm{MAPKK\_p\_671\_0\_}-\mathrm{k2}\mathrm{MAPKK\_dephospho\_ser\_cplx\_1123\_0\_})$ MAPKK_dephospho_ser_cplx_1123_0_ PPhosphatase2A_1114_0_ MAPKK_655_0_ MAPKK_dephospho_ser_1122_0_ 2 455.882352941 424.096385542 hotpink red kinetics_455_0_ * k3*MAPKK_dephospho_ser_cplx_1123_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{MAPKK\_dephospho\_ser\_cplx\_1123\_0\_}$ Ueki et al JBC 269(22) pp 15756-15761 1994 show hyperphosphorylation of craf, so this is there to dephosphorylate it. Identity of phosphatase is not known to me, but it may be PP2A like the rest, so I have made it so. PPhosphatase2A_1114_0_ craf_1_p_p_659_0_ craf_p_p_dephospho_cplx_1126_0_ craf_p_p_dephospho_1125_0_ 1 455.882352941 433.734939759 hotpink red kinetics_455_0_ * ( k1 * PPhosphatase2A_1114_0_*craf_1_p_p_659_0_ - k2 * craf_p_p_dephospho_cplx_1126_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PPhosphatase2A\_1114\_0\_}\mathrm{craf\_1\_p\_p\_659\_0\_}-\mathrm{k2}\mathrm{craf\_p\_p\_dephospho\_cplx\_1126\_0\_})$ craf_p_p_dephospho_cplx_1126_0_ PPhosphatase2A_1114_0_ craf_1_p_647_0_ craf_p_p_dephospho_1125_0_ 2 455.882352941 433.734939759 hotpink red kinetics_455_0_ * k3*craf_p_p_dephospho_cplx_1126_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{craf\_p\_p\_dephospho\_cplx\_1126\_0\_}$ PPhosphatase2A_1114_0_ craf_1_p_ser259_681_0_ deph_raf_ser259_cplx_1129_0_ deph_raf_ser259_1128_0_ 1 455.882352941 395.180722892 red hotpink kinetics_455_0_ * ( k1 * craf_1_p_ser259_681_0_*PPhosphatase2A_1114_0_ - k2 * deph_raf_ser259_cplx_1129_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{craf\_1\_p\_ser259\_681\_0\_}\mathrm{PPhosphatase2A\_1114\_0\_}-\mathrm{k2}\mathrm{deph\_raf\_ser259\_cplx\_1129\_0\_})$ deph_raf_ser259_cplx_1129_0_ PPhosphatase2A_1114_0_ craf_1_645_0_ deph_raf_ser259_1128_0_ 2 455.882352941 395.180722892 red hotpink kinetics_455_0_ * k3*deph_raf_ser259_cplx_1129_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{deph\_raf\_ser259\_cplx\_1129\_0\_}$ PP2A does most of the dephosph of I1 at basal Ca levels. See the review by Cohen in Ann Rev Biochem 1989. For now, lets halve Km. k1 was 3.3e-6, now 6.6e-6 PP2A_1131_0_ I1_p_921_0_ PP2A_dephospho_I1_cplx_1134_0_ PP2A_dephospho_I1_1133_0_ 1 470.588235294 404.819277108 red red kinetics_455_0_ * ( k1 * I1_p_921_0_*PP2A_1131_0_ - k2 * PP2A_dephospho_I1_cplx_1134_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{I1\_p\_921\_0\_}\mathrm{PP2A\_1131\_0\_}-\mathrm{k2}\mathrm{PP2A\_dephospho\_I1\_cplx\_1134\_0\_})$ PP2A_dephospho_I1_cplx_1134_0_ PP2A_1131_0_ I1_919_0_ PP2A_dephospho_I1_1133_0_ 2 470.588235294 404.819277108 red red kinetics_455_0_ * k3*PP2A_dephospho_I1_cplx_1134_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PP2A\_dephospho\_I1\_cplx\_1134\_0\_}$ k1 changed from 3.3e-6 to 6.6e-6 PP2A_1131_0_ PP1_I1_p_923_0_ PP2A_dephospho_PP1_I_p_cplx_1137_0_ PP2A_dephospho_PP1_I_p_1136_0_ 1 470.588235294 414.457831325 red red kinetics_455_0_ * ( k1 * PP2A_1131_0_*PP1_I1_p_923_0_ - k2 * PP2A_dephospho_PP1_I_p_cplx_1137_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{PP1\_I1\_p\_923\_0\_}-\mathrm{k2}\mathrm{PP2A\_dephospho\_PP1\_I\_p\_cplx\_1137\_0\_})$ PP2A_dephospho_PP1_I_p_cplx_1137_0_ PP2A_1131_0_ PP1_I1_925_0_ PP2A_dephospho_PP1_I_p_1136_0_ 2 470.588235294 414.457831325 red red kinetics_455_0_ * k3*PP2A_dephospho_PP1_I_p_cplx_1137_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PP2A\_dephospho\_PP1\_I\_p\_cplx\_1137\_0\_}$ PP2A_1131_0_ S6K_p_1304_0_ dephos_clus_S6K_cplx_1140_0_ dephos_clus_S6K_1139_0_ 1 470.588235294 424.096385542 red 25 kinetics_455_0_ * ( k1 * S6K_p_1304_0_*PP2A_1131_0_ - k2 * dephos_clus_S6K_cplx_1140_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{S6K\_p\_1304\_0\_}\mathrm{PP2A\_1131\_0\_}-\mathrm{k2}\mathrm{dephos\_clus\_S6K\_cplx\_1140\_0\_})$ dephos_clus_S6K_cplx_1140_0_ PP2A_1131_0_ S6K_1306_0_ dephos_clus_S6K_1139_0_ 2 470.588235294 424.096385542 red 25 kinetics_455_0_ * k3*dephos_clus_S6K_cplx_1140_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephos\_clus\_S6K\_cplx\_1140\_0\_}$ PP2A_1131_0_ S6K_thr_412_1308_0_ dephos_S6K_cplx_1143_0_ dephos_S6K_1142_0_ 1 470.588235294 433.734939759 red 25 kinetics_455_0_ * ( k1 * PP2A_1131_0_*S6K_thr_412_1308_0_ - k2 * dephos_S6K_cplx_1143_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{S6K\_thr\_412\_1308\_0\_}-\mathrm{k2}\mathrm{dephos\_S6K\_cplx\_1143\_0\_})$ dephos_S6K_cplx_1143_0_ PP2A_1131_0_ S6K_p_1304_0_ dephos_S6K_1142_0_ 2 470.588235294 433.734939759 red 25 kinetics_455_0_ * k3*dephos_S6K_cplx_1143_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephos\_S6K\_cplx\_1143\_0\_}$ PP2A_1131_0_ S6K_thr_252_1313_0_ dephosp_S6K_cplx_1146_0_ dephosp_S6K_1145_0_ 1 470.588235294 443.373493976 red 25 kinetics_455_0_ * ( k1 * S6K_thr_252_1313_0_*PP2A_1131_0_ - k2 * dephosp_S6K_cplx_1146_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{S6K\_thr\_252\_1313\_0\_}\mathrm{PP2A\_1131\_0\_}-\mathrm{k2}\mathrm{dephosp\_S6K\_cplx\_1146\_0\_})$ dephosp_S6K_cplx_1146_0_ PP2A_1131_0_ S6K_thr_412_1308_0_ dephosp_S6K_1145_0_ 2 470.588235294 443.373493976 red 25 kinetics_455_0_ * k3*dephosp_S6K_cplx_1146_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{dephosp\_S6K\_cplx\_1146\_0\_}$ PP2A_1131_0_ PIP3_AKT_t308_s473_1237_0_ Dephos_AKTser473_cplx_1149_0_ Dephos_AKTser473_1148_0_ 1 470.588235294 453.012048193 red 46 kinetics_455_0_ * ( k1 * PP2A_1131_0_*PIP3_AKT_t308_s473_1237_0_ - k2 * Dephos_AKTser473_cplx_1149_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{PIP3\_AKT\_t308\_s473\_1237\_0\_}-\mathrm{k2}\mathrm{Dephos\_AKTser473\_cplx\_1149\_0\_})$ Dephos_AKTser473_cplx_1149_0_ PP2A_1131_0_ PIP3_AKT_thr308_1235_0_ Dephos_AKTser473_1148_0_ 2 470.588235294 453.012048193 red 46 kinetics_455_0_ * k3*Dephos_AKTser473_cplx_1149_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Dephos\_AKTser473\_cplx\_1149\_0\_}$ PP2A_1131_0_ PIP3_AKT_thr308_1235_0_ Dephosph_AKTthr308_cplx_1152_0_ Dephosph_AKTthr308_1151_0_ 1 470.588235294 462.65060241 red 46 kinetics_455_0_ * ( k1 * PP2A_1131_0_*PIP3_AKT_thr308_1235_0_ - k2 * Dephosph_AKTthr308_cplx_1152_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{PIP3\_AKT\_thr308\_1235\_0\_}-\mathrm{k2}\mathrm{Dephosph\_AKTthr308\_cplx\_1152\_0\_})$ Dephosph_AKTthr308_cplx_1152_0_ PP2A_1131_0_ PIP3_AKT_1223_0_ Dephosph_AKTthr308_1151_0_ 2 470.588235294 462.65060241 red 46 kinetics_455_0_ * k3*Dephosph_AKTthr308_cplx_1152_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Dephosph\_AKTthr308\_cplx\_1152\_0\_}$ PP2A_1131_0_ eEFthr_56_1444_0_ eEF2thr_56_dephospho_cplx_1155_0_ eEF2thr_56_dephospho_1154_0_ 1 470.588235294 472.289156627 red 4 kinetics_455_0_ * ( k1 * PP2A_1131_0_*eEFthr_56_1444_0_ - k2 * eEF2thr_56_dephospho_cplx_1155_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{eEFthr\_56\_1444\_0\_}-\mathrm{k2}\mathrm{eEF2thr\_56\_dephospho\_cplx\_1155\_0\_})$ eEF2thr_56_dephospho_cplx_1155_0_ PP2A_1131_0_ eEF2_1442_0_ eEF2thr_56_dephospho_1154_0_ 2 470.588235294 472.289156627 red 4 kinetics_455_0_ * k3*eEF2thr_56_dephospho_cplx_1155_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{eEF2thr\_56\_dephospho\_cplx\_1155\_0\_}$ PP2A_1131_0_ _4E_BP_t37_46_s65_1334_0_ PP2A_4E_BP_p_p_cplx_1158_0_ PP2A_4E_BP_p_p_1157_0_ 1 470.588235294 481.927710843 red 4 kinetics_455_0_ * ( k1 * PP2A_1131_0_*_4E_BP_t37_46_s65_1334_0_ - k2 * PP2A_4E_BP_p_p_cplx_1158_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{\_4E\_BP\_t37\_46\_s65\_1334\_0\_}-\mathrm{k2}\mathrm{PP2A\_4E\_BP\_p\_p\_cplx\_1158\_0\_})$ PP2A_4E_BP_p_p_cplx_1158_0_ PP2A_1131_0_ _4E_BP_t37_46_1342_0_ PP2A_4E_BP_p_p_1157_0_ 2 470.588235294 481.927710843 red 4 kinetics_455_0_ * k3*PP2A_4E_BP_p_p_cplx_1158_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PP2A\_4E\_BP\_p\_p\_cplx\_1158\_0\_}$ PP2A_1131_0_ _4E_BP_t37_46_1342_0_ PP2A_4E_BP_p_cplx_1161_0_ PP2A_4E_BP_p_1160_0_ 1 470.588235294 491.56626506 red 4 kinetics_455_0_ * ( k1 * PP2A_1131_0_*_4E_BP_t37_46_1342_0_ - k2 * PP2A_4E_BP_p_cplx_1161_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{\_4E\_BP\_t37\_46\_1342\_0\_}-\mathrm{k2}\mathrm{PP2A\_4E\_BP\_p\_cplx\_1161\_0\_})$ PP2A_4E_BP_p_cplx_1161_0_ PP2A_1131_0_ _4E_BP_1332_0_ PP2A_4E_BP_p_1160_0_ 2 470.588235294 491.56626506 red 4 kinetics_455_0_ * k3*PP2A_4E_BP_p_cplx_1161_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PP2A\_4E\_BP\_p\_cplx\_1161\_0\_}$ PP2A_1131_0_ eIF4E_BP_t37_46_s65_1340_0_ PP2A_4E_BP_cplx_1164_0_ PP2A_4E_BP_1163_0_ 1 470.588235294 501.204819277 red 62 kinetics_455_0_ * ( k1 * PP2A_1131_0_*eIF4E_BP_t37_46_s65_1340_0_ - k2 * PP2A_4E_BP_cplx_1164_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PP2A\_1131\_0\_}\mathrm{eIF4E\_BP\_t37\_46\_s65\_1340\_0\_}-\mathrm{k2}\mathrm{PP2A\_4E\_BP\_cplx\_1164\_0\_})$ PP2A_4E_BP_cplx_1164_0_ PP2A_1131_0_ eIF4E_BP_thr37_46_1338_0_ PP2A_4E_BP_1163_0_ 2 470.588235294 501.204819277 red 62 kinetics_455_0_ * k3*PP2A_4E_BP_cplx_1164_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PP2A\_4E\_BP\_cplx\_1164\_0\_}$ PP2A_1131_0_ eIF4E_BP_thr37_46_1338_0_ PP2A_4EBP_cplx_1167_0_ PP2A_4EBP_1166_0_ 1 470.588235294 510.843373494 red 62 kinetics_455_0_ * ( k1 * eIF4E_BP_thr37_46_1338_0_*PP2A_1131_0_ - k2 * PP2A_4EBP_cplx_1167_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{eIF4E\_BP\_thr37\_46\_1338\_0\_}\mathrm{PP2A\_1131\_0\_}-\mathrm{k2}\mathrm{PP2A\_4EBP\_cplx\_1167\_0\_})$ PP2A_4EBP_cplx_1167_0_ PP2A_1131_0_ eIF4E_BP_1336_0_ PP2A_4EBP_1166_0_ 2 470.588235294 510.843373494 red 62 kinetics_455_0_ * k3*PP2A_4EBP_cplx_1167_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PP2A\_4EBP\_cplx\_1167\_0\_}$ PP2A_1131_0_ Internal_mGluR_p_1530_0_ mGluR_dephosph_cplx_1170_0_ mGluR_dephosph_1169_0_ 1 470.588235294 520.481927711 23 black kinetics_455_0_ * ( k1 * Internal_mGluR_p_1530_0_*PP2A_1131_0_ - k2 * mGluR_dephosph_cplx_1170_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Internal\_mGluR\_p\_1530\_0\_}\mathrm{PP2A\_1131\_0\_}-\mathrm{k2}\mathrm{mGluR\_dephosph\_cplx\_1170\_0\_})$ mGluR_dephosph_cplx_1170_0_ PP2A_1131_0_ Internal_mGluR_1528_0_ mGluR_dephosph_1169_0_ 2 470.588235294 520.481927711 23 black kinetics_455_0_ * k3*mGluR_dephosph_cplx_1170_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{mGluR\_dephosph\_cplx\_1170\_0\_}$ PDK1_1182_0_ S6K_thr_412_1308_0_ S6K_phospho_cplx_1185_0_ S6K_phospho_1184_0_ 1 794.117647059 404.819277108 red 37 kinetics_455_0_ * ( k1 * S6K_thr_412_1308_0_*PDK1_1182_0_ - k2 * S6K_phospho_cplx_1185_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{S6K\_thr\_412\_1308\_0\_}\mathrm{PDK1\_1182\_0\_}-\mathrm{k2}\mathrm{S6K\_phospho\_cplx\_1185\_0\_})$ S6K_phospho_cplx_1185_0_ PDK1_1182_0_ S6K_thr_252_1313_0_ S6K_phospho_1184_0_ 2 794.117647059 404.819277108 red 37 kinetics_455_0_ * k3*S6K_phospho_cplx_1185_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{S6K\_phospho\_cplx\_1185\_0\_}$ SHC_p_Grb2_Gab1_PI3K_clx_1187_0_ PIP2_613_0_ Phospho_cplx_1190_0_ Phospho_1189_0_ 1 808.823529412 404.819277108 red brown kinetics_455_0_ * ( k1 * SHC_p_Grb2_Gab1_PI3K_clx_1187_0_*PIP2_613_0_ - k2 * Phospho_cplx_1190_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{SHC\_p\_Grb2\_Gab1\_PI3K\_clx\_1187\_0\_}\mathrm{PIP2\_613\_0\_}-\mathrm{k2}\mathrm{Phospho\_cplx\_1190\_0\_})$ Phospho_cplx_1190_0_ SHC_p_Grb2_Gab1_PI3K_clx_1187_0_ PIP3_1180_0_ Phospho_1189_0_ 2 808.823529412 404.819277108 red brown kinetics_455_0_ * k3*Phospho_cplx_1190_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Phospho\_cplx\_1190\_0\_}$ PI3K_basal_1194_0_ PIP2_613_0_ basal_phosp_cplx_1197_0_ basal_phosp_1196_0_ 1 838.235294118 404.819277108 red 10 kinetics_455_0_ * ( k1 * PI3K_basal_1194_0_*PIP2_613_0_ - k2 * basal_phosp_cplx_1197_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PI3K\_basal\_1194\_0\_}\mathrm{PIP2\_613\_0\_}-\mathrm{k2}\mathrm{basal\_phosp\_cplx\_1197\_0\_})$ basal_phosp_cplx_1197_0_ PI3K_basal_1194_0_ PIP3_1180_0_ basal_phosp_1196_0_ 2 838.235294118 404.819277108 red 10 kinetics_455_0_ * k3*basal_phosp_cplx_1197_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{basal\_phosp\_cplx\_1197\_0\_}$ PTEN_1203_0_ PIP3_1180_0_ PIP3_dephosp_cplx_1206_0_ PIP3_dephosp_1205_0_ 1 757.352941176 510.843373494 red 37 kinetics_455_0_ * ( k1 * PTEN_1203_0_*PIP3_1180_0_ - k2 * PIP3_dephosp_cplx_1206_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PTEN\_1203\_0\_}\mathrm{PIP3\_1180\_0\_}-\mathrm{k2}\mathrm{PIP3\_dephosp\_cplx\_1206\_0\_})$ PIP3_dephosp_cplx_1206_0_ PTEN_1203_0_ PIP2_613_0_ PIP3_dephosp_1205_0_ 2 757.352941176 510.843373494 red 37 kinetics_455_0_ * k3*PIP3_dephosp_cplx_1206_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PIP3\_dephosp\_cplx\_1206\_0\_}$ Ras_GTP_PI3K_1214_0_ PIP2_613_0_ PIP2_phospho_Ras_GTP_cplx_1217_0_ PIP2_phospho_Ras_GTP_1216_0_ 1 794.117647059 510.843373494 red 31 kinetics_455_0_ * ( k1 * PIP2_613_0_*Ras_GTP_PI3K_1214_0_ - k2 * PIP2_phospho_Ras_GTP_cplx_1217_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP2\_613\_0\_}\mathrm{Ras\_GTP\_PI3K\_1214\_0\_}-\mathrm{k2}\mathrm{PIP2\_phospho\_Ras\_GTP\_cplx\_1217\_0\_})$ PIP2_phospho_Ras_GTP_cplx_1217_0_ Ras_GTP_PI3K_1214_0_ PIP3_1180_0_ PIP2_phospho_Ras_GTP_1216_0_ 2 794.117647059 510.843373494 red 31 kinetics_455_0_ * k3*PIP2_phospho_Ras_GTP_cplx_1217_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PIP2\_phospho\_Ras\_GTP\_cplx\_1217\_0\_}$ PIP3_PDK1_1225_0_ PIP3_AKT_1223_0_ phospho_thr308_cplx_1228_0_ phospho_thr308_1227_0_ 1 897.058823529 404.819277108 red 9 kinetics_455_0_ * ( k1 * PIP3_PDK1_1225_0_*PIP3_AKT_1223_0_ - k2 * phospho_thr308_cplx_1228_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP3\_PDK1\_1225\_0\_}\mathrm{PIP3\_AKT\_1223\_0\_}-\mathrm{k2}\mathrm{phospho\_thr308\_cplx\_1228\_0\_})$ phospho_thr308_cplx_1228_0_ PIP3_PDK1_1225_0_ PIP3_AKT_thr308_1235_0_ phospho_thr308_1227_0_ 2 897.058823529 404.819277108 red 9 kinetics_455_0_ * k3*phospho_thr308_cplx_1228_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{phospho\_thr308\_cplx\_1228\_0\_}$ PIP3_PDK2_1230_0_ PIP3_AKT_thr308_1235_0_ phosp_AKTser473_cplx_1233_0_ phosp_AKTser473_1232_0_ 1 911.764705882 404.819277108 red 39 kinetics_455_0_ * ( k1 * PIP3_AKT_thr308_1235_0_*PIP3_PDK2_1230_0_ - k2 * phosp_AKTser473_cplx_1233_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP3\_AKT\_thr308\_1235\_0\_}\mathrm{PIP3\_PDK2\_1230\_0\_}-\mathrm{k2}\mathrm{phosp\_AKTser473\_cplx\_1233\_0\_})$ phosp_AKTser473_cplx_1233_0_ PIP3_PDK2_1230_0_ PIP3_AKT_t308_s473_1237_0_ phosp_AKTser473_1232_0_ 2 911.764705882 404.819277108 red 39 kinetics_455_0_ * k3*phosp_AKTser473_cplx_1233_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{phosp\_AKTser473\_cplx\_1233\_0\_}$ PIP3_AKT_t308_s473_1237_0_ TSC1_TSC2_1485_0_ TSC2_phospho_cplx_1240_0_ TSC2_phospho_1239_0_ 1 941.176470588 404.819277108 red 25 kinetics_455_0_ * ( k1 * PIP3_AKT_t308_s473_1237_0_*TSC1_TSC2_1485_0_ - k2 * TSC2_phospho_cplx_1240_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP3\_AKT\_t308\_s473\_1237\_0\_}\mathrm{TSC1\_TSC2\_1485\_0\_}-\mathrm{k2}\mathrm{TSC2\_phospho\_cplx\_1240\_0\_})$ TSC2_phospho_cplx_1240_0_ PIP3_AKT_t308_s473_1237_0_ TSC1_TSC2_p_1483_0_ TSC2_phospho_1239_0_ 2 941.176470588 404.819277108 red 25 kinetics_455_0_ * k3*TSC2_phospho_cplx_1240_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{TSC2\_phospho\_cplx\_1240\_0\_}$ PIP3_AKT_t308_s473_1237_0_ craf_1_645_0_ Enz_cplx_1243_0_ Enz_1242_0_ 1 941.176470588 414.457831325 black 19 kinetics_455_0_ * ( k1 * PIP3_AKT_t308_s473_1237_0_*craf_1_645_0_ - k2 * Enz_cplx_1243_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP3\_AKT\_t308\_s473\_1237\_0\_}\mathrm{craf\_1\_645\_0\_}-\mathrm{k2}\mathrm{Enz\_cplx\_1243\_0\_})$ Enz_cplx_1243_0_ PIP3_AKT_t308_s473_1237_0_ craf_1_p_ser259_681_0_ Enz_1242_0_ 2 941.176470588 414.457831325 black 19 kinetics_455_0_ * k3*Enz_cplx_1243_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Enz\_cplx\_1243\_0\_}$ BDNF_TrKB2_p_clx_1261_0_ PLC_g_791_0_ PLC_g_phospho_cplx_1264_0_ PLC_g_phospho_1263_0_ 1 58.8235294118 597.590361446 red red kinetics_455_0_ * ( k1 * BDNF_TrKB2_p_clx_1261_0_*PLC_g_791_0_ - k2 * PLC_g_phospho_cplx_1264_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{BDNF\_TrKB2\_p\_clx\_1261\_0\_}\mathrm{PLC\_g\_791\_0\_}-\mathrm{k2}\mathrm{PLC\_g\_phospho\_cplx\_1264\_0\_})$ PLC_g_phospho_cplx_1264_0_ BDNF_TrKB2_p_clx_1261_0_ PLC_g_p_793_0_ PLC_g_phospho_1263_0_ 2 58.8235294118 597.590361446 red red kinetics_455_0_ * k3*PLC_g_phospho_cplx_1264_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{PLC\_g\_phospho\_cplx\_1264\_0\_}$ BDNF_TrKB2_p_clx_1261_0_ SHC_761_0_ SHC_phospho_cplx_1267_0_ SHC_phospho_1266_0_ 1 58.8235294118 607.228915663 red red kinetics_455_0_ * ( k1 * SHC_761_0_*BDNF_TrKB2_p_clx_1261_0_ - k2 * SHC_phospho_cplx_1267_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{SHC\_761\_0\_}\mathrm{BDNF\_TrKB2\_p\_clx\_1261\_0\_}-\mathrm{k2}\mathrm{SHC\_phospho\_cplx\_1267\_0\_})$ SHC_phospho_cplx_1267_0_ BDNF_TrKB2_p_clx_1261_0_ SHC_p_763_0_ SHC_phospho_1266_0_ 2 58.8235294118 607.228915663 red red kinetics_455_0_ * k3*SHC_phospho_cplx_1267_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{SHC\_phospho\_cplx\_1267\_0\_}$ TOR_Rheb_GTP_clx_1287_0_ S6K_p_1304_0_ S6K_phospho_cplx_1290_0_ S6K_phospho_1289_0_ 1 191.176470588 597.590361446 red 42 kinetics_455_0_ * ( k1 * S6K_p_1304_0_*TOR_Rheb_GTP_clx_1287_0_ - k2 * S6K_phospho_cplx_1290_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{S6K\_p\_1304\_0\_}\mathrm{TOR\_Rheb\_GTP\_clx\_1287\_0\_}-\mathrm{k2}\mathrm{S6K\_phospho\_cplx\_1290\_0\_})$ S6K_phospho_cplx_1290_0_ TOR_Rheb_GTP_clx_1287_0_ S6K_thr_412_1308_0_ S6K_phospho_1289_0_ 2 191.176470588 597.590361446 red 42 kinetics_455_0_ * k3*S6K_phospho_cplx_1290_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{S6K\_phospho\_cplx\_1290\_0\_}$ TOR_Rheb_GTP_clx_1287_0_ eIF4E_BP_1336_0_ TOR_4E_BP_phospho_cplx_1293_0_ TOR_4E_BP_phospho_1292_0_ 1 191.176470588 607.228915663 red 44 kinetics_455_0_ * ( k1 * eIF4E_BP_1336_0_*TOR_Rheb_GTP_clx_1287_0_ - k2 * TOR_4E_BP_phospho_cplx_1293_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{eIF4E\_BP\_1336\_0\_}\mathrm{TOR\_Rheb\_GTP\_clx\_1287\_0\_}-\mathrm{k2}\mathrm{TOR\_4E\_BP\_phospho\_cplx\_1293\_0\_})$ TOR_4E_BP_phospho_cplx_1293_0_ TOR_Rheb_GTP_clx_1287_0_ eIF4E_BP_thr37_46_1338_0_ TOR_4E_BP_phospho_1292_0_ 2 191.176470588 607.228915663 red 44 kinetics_455_0_ * k3*TOR_4E_BP_phospho_cplx_1293_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{TOR\_4E\_BP\_phospho\_cplx\_1293\_0\_}$ TOR_Rheb_GTP_clx_1287_0_ _4E_BP_1332_0_ TOR_4E_BP_p_cplx_1296_0_ TOR_4E_BP_p_1295_0_ 1 191.176470588 616.86746988 red 44 kinetics_455_0_ * ( k1 * _4E_BP_1332_0_*TOR_Rheb_GTP_clx_1287_0_ - k2 * TOR_4E_BP_p_cplx_1296_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{\_4E\_BP\_1332\_0\_}\mathrm{TOR\_Rheb\_GTP\_clx\_1287\_0\_}-\mathrm{k2}\mathrm{TOR\_4E\_BP\_p\_cplx\_1296\_0\_})$ TOR_4E_BP_p_cplx_1296_0_ TOR_Rheb_GTP_clx_1287_0_ _4E_BP_t37_46_1342_0_ TOR_4E_BP_p_1295_0_ 2 191.176470588 616.86746988 red 44 kinetics_455_0_ * k3*TOR_4E_BP_p_cplx_1296_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{TOR\_4E\_BP\_p\_cplx\_1296\_0\_}$ S6K_thr_412_1308_0_ _40S_inact_1472_0_ S6_phos_cplx_1311_0_ S6_phos_1310_0_ 1 323.529411765 597.590361446 red 48 kinetics_455_0_ * ( k1 * _40S_inact_1472_0_*S6K_thr_412_1308_0_ - k2 * S6_phos_cplx_1311_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{\_40S\_inact\_1472\_0\_}\mathrm{S6K\_thr\_412\_1308\_0\_}-\mathrm{k2}\mathrm{S6\_phos\_cplx\_1311\_0\_})$ S6_phos_cplx_1311_0_ S6K_thr_412_1308_0_ _40S_1474_0_ S6_phos_1310_0_ 2 323.529411765 597.590361446 red 48 kinetics_455_0_ * k3*S6_phos_cplx_1311_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{S6\_phos\_cplx\_1311\_0\_}$ S6K_thr_252_1313_0_ CaMKIII_1402_0_ CaMKIII_phospho_cplx_1316_0_ CaMKIII_phospho_1315_0_ 1 338.235294118 597.590361446 red 6 kinetics_455_0_ * ( k1 * S6K_thr_252_1313_0_*CaMKIII_1402_0_ - k2 * CaMKIII_phospho_cplx_1316_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{S6K\_thr\_252\_1313\_0\_}\mathrm{CaMKIII\_1402\_0\_}-\mathrm{k2}\mathrm{CaMKIII\_phospho\_cplx\_1316\_0\_})$ CaMKIII_phospho_cplx_1316_0_ S6K_thr_252_1313_0_ CaMKIII_p_1414_0_ CaMKIII_phospho_1315_0_ 2 338.235294118 597.590361446 red 6 kinetics_455_0_ * k3*CaMKIII_phospho_cplx_1316_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{CaMKIII\_phospho\_cplx\_1316\_0\_}$ S6K_thr_252_1313_0_ _40S_inact_1472_0_ S6_phospho_cplx_1319_0_ S6_phospho_1318_0_ 1 338.235294118 607.228915663 red 4 kinetics_455_0_ * ( k1 * _40S_inact_1472_0_*S6K_thr_252_1313_0_ - k2 * S6_phospho_cplx_1319_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{\_40S\_inact\_1472\_0\_}\mathrm{S6K\_thr\_252\_1313\_0\_}-\mathrm{k2}\mathrm{S6\_phospho\_cplx\_1319\_0\_})$ S6_phospho_cplx_1319_0_ S6K_thr_252_1313_0_ _40S_1474_0_ S6_phospho_1318_0_ 2 338.235294118 607.228915663 red 4 kinetics_455_0_ * k3*S6_phospho_cplx_1319_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{S6\_phospho\_cplx\_1319\_0\_}$ S6K_basal_1321_0_ CaMKIII_1402_0_ CaMKIII_basal_cplx_1324_0_ CaMKIII_basal_1323_0_ 1 352.941176471 597.590361446 red 45 kinetics_455_0_ * ( k1 * S6K_basal_1321_0_*CaMKIII_1402_0_ - k2 * CaMKIII_basal_cplx_1324_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{S6K\_basal\_1321\_0\_}\mathrm{CaMKIII\_1402\_0\_}-\mathrm{k2}\mathrm{CaMKIII\_basal\_cplx\_1324\_0\_})$ CaMKIII_basal_cplx_1324_0_ S6K_basal_1321_0_ CaMKIII_p_1414_0_ CaMKIII_basal_1323_0_ 2 352.941176471 597.590361446 red 45 kinetics_455_0_ * k3*CaMKIII_basal_cplx_1324_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{CaMKIII\_basal\_cplx\_1324\_0\_}$ CaMKIII_CaM_Ca4_1404_0_ eEF2_1442_0_ phospho_cplx_1407_0_ phospho_1406_0_ 1 14.7058823529 790.361445783 red 58 kinetics_455_0_ * ( k1 * eEF2_1442_0_*CaMKIII_CaM_Ca4_1404_0_ - k2 * phospho_cplx_1407_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{eEF2\_1442\_0\_}\mathrm{CaMKIII\_CaM\_Ca4\_1404\_0\_}-\mathrm{k2}\mathrm{phospho\_cplx\_1407\_0\_})$ phospho_cplx_1407_0_ CaMKIII_CaM_Ca4_1404_0_ eEFthr_56_1444_0_ phospho_1406_0_ 2 14.7058823529 790.361445783 red 58 kinetics_455_0_ * k3*phospho_cplx_1407_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{phospho\_cplx\_1407\_0\_}$ CaMKIII_basal_1409_0_ eEF2_1442_0_ eEF2thr56_basal_cplx_1412_0_ eEF2thr56_basal_1411_0_ 1 29.4117647059 790.361445783 red 45 kinetics_455_0_ * ( k1 * CaMKIII_basal_1409_0_*eEF2_1442_0_ - k2 * eEF2thr56_basal_cplx_1412_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{CaMKIII\_basal\_1409\_0\_}\mathrm{eEF2\_1442\_0\_}-\mathrm{k2}\mathrm{eEF2thr56\_basal\_cplx\_1412\_0\_})$ eEF2thr56_basal_cplx_1412_0_ CaMKIII_basal_1409_0_ eEFthr_56_1444_0_ eEF2thr56_basal_1411_0_ 2 29.4117647059 790.361445783 red 45 kinetics_455_0_ * k3*eEF2thr56_basal_cplx_1412_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{eEF2thr56\_basal\_cplx\_1412\_0\_}$ Translation_clx_1448_0_ AA_1370_0_ pro_syn_cplx_1451_0_ pro_syn_1450_0_ 1 338.235294118 790.361445783 red 52 kinetics_455_0_ * ( k1 * Translation_clx_1448_0_*AA_1370_0_ - k2 * pro_syn_cplx_1451_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Translation\_clx\_1448\_0\_}\mathrm{AA\_1370\_0\_}-\mathrm{k2}\mathrm{pro\_syn\_cplx\_1451\_0\_})$ pro_syn_cplx_1451_0_ Translation_clx_1448_0_ peptide_1372_0_ pro_syn_1450_0_ 2 338.235294118 790.361445783 red 52 kinetics_455_0_ * k3*pro_syn_cplx_1451_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{pro\_syn\_cplx\_1451\_0\_}$ Translation_clx_1448_0_ rad_AA_1378_0_ rad_pro_syn_cplx_1454_0_ rad_pro_syn_1453_0_ 1 338.235294118 800.0 red 52 kinetics_455_0_ * ( k1 * Translation_clx_1448_0_*rad_AA_1378_0_ - k2 * rad_pro_syn_cplx_1454_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Translation\_clx\_1448\_0\_}\mathrm{rad\_AA\_1378\_0\_}-\mathrm{k2}\mathrm{rad\_pro\_syn\_cplx\_1454\_0\_})$ rad_pro_syn_cplx_1454_0_ Translation_clx_1448_0_ rad_peptide_1380_0_ rad_pro_syn_1453_0_ 2 338.235294118 800.0 red 52 kinetics_455_0_ * k3*rad_pro_syn_cplx_1454_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{rad\_pro\_syn\_cplx\_1454\_0\_}$ Basal_Translation_1458_0_ AA_1370_0_ basal_syn_cplx_1461_0_ basal_syn_1460_0_ 1 367.647058824 790.361445783 red 53 kinetics_455_0_ * ( k1 * Basal_Translation_1458_0_*AA_1370_0_ - k2 * basal_syn_cplx_1461_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Basal\_Translation\_1458\_0\_}\mathrm{AA\_1370\_0\_}-\mathrm{k2}\mathrm{basal\_syn\_cplx\_1461\_0\_})$ basal_syn_cplx_1461_0_ Basal_Translation_1458_0_ peptide_1372_0_ basal_syn_1460_0_ 2 367.647058824 790.361445783 red 53 kinetics_455_0_ * k3*basal_syn_cplx_1461_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{basal\_syn\_cplx\_1461\_0\_}$ Basal_Translation_1458_0_ rad_AA_1378_0_ rad_basal_syn_cplx_1464_0_ rad_basal_syn_1463_0_ 1 367.647058824 800.0 red 53 kinetics_455_0_ * ( k1 * Basal_Translation_1458_0_*rad_AA_1378_0_ - k2 * rad_basal_syn_cplx_1464_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Basal\_Translation\_1458\_0\_}\mathrm{rad\_AA\_1378\_0\_}-\mathrm{k2}\mathrm{rad\_basal\_syn\_cplx\_1464\_0\_})$ rad_basal_syn_cplx_1464_0_ Basal_Translation_1458_0_ peptide_1372_0_ rad_basal_syn_1463_0_ 2 367.647058824 800.0 red 53 kinetics_455_0_ * k3*rad_basal_syn_cplx_1464_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{rad\_basal\_syn\_cplx\_1464\_0\_}$ _40S_basal_1476_0_ _40S_inact_1472_0_ basal_cplx_1479_0_ basal_1478_0_ 1 470.588235294 790.361445783 red 44 kinetics_455_0_ * ( k1 * _40S_inact_1472_0_*_40S_basal_1476_0_ - k2 * basal_cplx_1479_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{\_40S\_inact\_1472\_0\_}\mathrm{\_40S\_basal\_1476\_0\_}-\mathrm{k2}\mathrm{basal\_cplx\_1479\_0\_})$ basal_cplx_1479_0_ _40S_basal_1476_0_ _40S_1474_0_ basal_1478_0_ 2 470.588235294 790.361445783 red 44 kinetics_455_0_ * k3*basal_cplx_1479_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{basal\_cplx\_1479\_0\_}$ TSC1_TSC2_1485_0_ Rheb_GTP_1281_0_ TSC2phospho_cplx_1488_0_ TSC2phospho_1487_0_ 1 602.941176471 790.361445783 red 51 kinetics_455_0_ * ( k1 * Rheb_GTP_1281_0_*TSC1_TSC2_1485_0_ - k2 * TSC2phospho_cplx_1488_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{Rheb\_GTP\_1281\_0\_}\mathrm{TSC1\_TSC2\_1485\_0\_}-\mathrm{k2}\mathrm{TSC2phospho\_cplx\_1488\_0\_})$ TSC2phospho_cplx_1488_0_ TSC1_TSC2_1485_0_ Rheb_GDP_1283_0_ TSC2phospho_1487_0_ 2 602.941176471 790.361445783 red 51 kinetics_455_0_ * k3*TSC2phospho_cplx_1488_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{TSC2phospho\_cplx\_1488\_0\_}$ L_dot_mGluR_p_dot_Homer_dot_PIKE_L_dot_PI3K_1502_0_ PIP2_613_0_ Enz_cplx_1505_0_ Enz_1504_0_ 1 794.117647059 790.361445783 27 23 kinetics_455_0_ * ( k1 * PIP2_613_0_*L_dot_mGluR_p_dot_Homer_dot_PIKE_L_dot_PI3K_1502_0_ - k2 * Enz_cplx_1505_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{PIP2\_613\_0\_}\mathrm{L\_dot\_mGluR\_p\_dot\_Homer\_dot\_PIKE\_L\_dot\_PI3K\_1502\_0\_}-\mathrm{k2}\mathrm{Enz\_cplx\_1505\_0\_})$ Enz_cplx_1505_0_ L_dot_mGluR_p_dot_Homer_dot_PIKE_L_dot_PI3K_1502_0_ PIP3_1180_0_ Enz_1504_0_ 2 794.117647059 790.361445783 27 23 kinetics_455_0_ * k3*Enz_cplx_1505_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{Enz\_cplx\_1505\_0\_}$ GRK_1515_0_ Rec_Glu_1070_0_ GRK_binding_cplx_1518_0_ GRK_binding_1517_0_ 1 882.352941176 790.361445783 20 black kinetics_455_0_ * ( k1 * GRK_1515_0_*Rec_Glu_1070_0_ - k2 * GRK_binding_cplx_1518_0_ ) $\mathrm{kinetics\_455\_0\_}(\mathrm{k1}\mathrm{GRK\_1515\_0\_}\mathrm{Rec\_Glu\_1070\_0\_}-\mathrm{k2}\mathrm{GRK\_binding\_cplx\_1518\_0\_})$ GRK_binding_cplx_1518_0_ GRK_1515_0_ L_dot_mGluR_p_1520_0_ GRK_binding_1517_0_ 2 882.352941176 790.361445783 20 black kinetics_455_0_ * k3*GRK_binding_cplx_1518_0_ $\mathrm{kinetics\_455\_0\_}\mathrm{k3}\mathrm{GRK\_binding\_cplx\_1518\_0\_}$ kinetics_455_0_ kinetics_455_0_ 1 kinetics_455_0_ kinetics_455_0_ 1 kinetics_455_0_ kinetics_455_0_ 3 kinetics_455_0_ kinetics_455_0_ 4 kinetics_455_0_ kinetics_455_0_ 4 kinetics_455_0_ kinetics_455_0_ 0 kinetics_455_0_ kinetics_455_0_ 2 kinetics_455_0_ kinetics_455_0_ 3 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 7 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 5 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 4 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 2 kinetics_455_0_ kinetics_455_0_ 5 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 9 kinetics_455_0_ kinetics_455_0_ 9 kinetics_455_0_ kinetics_455_0_ 9 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 7 kinetics_455_0_ kinetics_455_0_ 1 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 7 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8 kinetics_455_0_ kinetics_455_0_ 8