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Enzyme List for pathway Shared_Object_mkp1_feedback_effects (Pathway Number 32)

 Molecule Name/
Site Name 		Km (uM) kcat (1/s)Ratio
(k2/k3)		Enzyme TypeSubstrate Product
1 Enzyme Activity:
craf**-deph

Enzyme Molecule:
PPhosphatase2A		15.656664.16667explicit E-S complexcraf-1**
craf-1*
  Ueki K, Matsuda S, Tobe K, Gotoh Y, Tamemoto H, Yachi M, Akanuma Y, Yazaki Y, Nishida E, Kadowaki T. (1994) J Biol Chem. 269(22):15756-61show hyperphosphorylation of craf, so this is there to dephosphorylate it. Identity of phosphatase is assumed to be PP2A.
2 Enzyme Activity:
craf-deph

Enzyme Molecule:
PPhosphatase2A		15.656664.16667explicit E-S complexcraf-1*
craf-1
  See parent PPhosphatase2A for parms
3 Enzyme Activity:
MAPK*

Enzyme Molecule:
MAPK*		25.641204explicit E-S complexPLA2-cytosolic
PLA2*
  Km for MBP = 25 uM at 50 uM ATP, Km for ATP = 58 uM at 1mg/ml MBP (huge excess of substrate), Vmax = 4124 pmol/min/ml at a concentartion of 125 pmol/ml of enzyme. Numbers are from pp. 54 Sanghera JS, Paddon HB, Bader SA, Pelech SL. (1990) J Biol Chem. 265(1):52-7. From Nemenoff RA, Winitz S, Qian NX, Van Putten V, Johnson GL, Heasley LE. (1993) J Biol Chem. 268(3):1960-1964 - using Sanghera's 1e-4 ratio of MAPK to protein, we get k3 = 7/sec from 1000 pmol/min/mg total protein in fig 5 I take the Vmax to be higher for PLA2 given the fold activation of PLA2 by MAPK. This is actually a balance term between MAPK and the dephosphorylation step.
4 Enzyme Activity:
MAPK*-feedback

Enzyme Molecule:
MAPK*		25.641104explicit E-S complexcraf-1*
craf-1**
  Ueki K, Matsuda S, Tobe K, Gotoh Y, Tamemoto H, Yachi M, Akanuma Y, Yazaki Y, Nishida E, Kadowaki T. (1994) J Biol Chem. 269(22):15756-15761 show the presence of this step, but not the rate constants, which are derived from Sanghera JS, Paddon HB, Bader SA, Pelech SL. (1990) J Biol Chem. 265(1):52-57; follow the derivation in the MAPK* notes.
5 Enzyme Activity:
MAPKK-deph

Enzyme Molecule:
PPhosphatase2A		15.656664.16667explicit E-S complexMAPKK*
MAPKK-ser
  See: Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, Avruch J. (1992) Nature 358(6385):417-21. Ahn NG, Seger R, Krebs EG. (1992) Curr Opin Cell Biol. 4(6):992-999 for this pathway. Refer parent PPhosphatase2A for parameters.
6 Enzyme Activity:
MAPKK-deph-ser

Enzyme Molecule:
PPhosphatase2A		15.656664.16667explicit E-S complexMAPKK-ser
MAPKK
  See parent PPhostphatase2A description for rate details
7 Enzyme Activity:
MKP-1-phosph

Enzyme Molecule:
MAPK*		25.64114explicit E-S complexMKP-1
MKP-1-ser359*
  3 Feb 2000. MAPK rates based on Sanghera JS, Paddon HB, Bader SA, Pelech SL. (1990) 265(1):52-57. The Vmax is scaled down 10 fold to match the time-course of phosph by MAPK, from Brondello JM, Pouyssegur J, McKenzie FR. (1999) Science 286(5449):2514-2517.
8 Enzyme Activity:
MKP-1-phosph2

Enzyme Molecule:
MAPK*		25.64114explicit E-S complexMKP-1-ser359*
MKP-1**
  3 Feb 2000. MAPK rates based on Sanghera JS, Paddon HB, Bader SA, Pelech SL. (1990) 265(1):52-57. The Vmax is scaled down 10 fold to match the time-course of phosph by MAPK, from Brondello JM, Pouyssegur J, McKenzie FR. (1999) Science 286(5449):2514-2517.
9 Enzyme Activity:
MKP1-thr-deph

Enzyme Molecule:
MKP-1		0.066714Classical Michaelis-Menten
V = Etot.S.Kcat/Km+S		MAPK*
MAPK-tyr
  See MKP1-tyr-deph
10 Enzyme Activity:
MKP1-tyr-deph

Enzyme Molecule:
MKP-1		0.066714Classical Michaelis-Menten
V = Etot.S.Kcat/Km+S		MAPK-tyr
MAPK
  The original kinetics from Bhalla US and Iyengar R. (1999) Science 283(5400):381-387 have now been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. The main constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. See Charles CH, Sun H, Lau LF, Tonks NK. (1993) Proc Natl Acad Sci U S A. 90(11):5292-5296 and Charles CH, Abler AS, Lau LF. (1992) Oncogene 7(1):187-190. Effective Km : 67 nM kcat = 1.43 umol/min/mg.
11 Enzyme Activity:
MKP2-thr-deph

Enzyme Molecule:
MKP-2		0.066714explicit E-S complexMAPK*
MAPK-tyr
  See MKP2-tyr-deph
12 Enzyme Activity:
MKP2-tyr-deph

Enzyme Molecule:
MKP-2		0.066714explicit E-S complexMAPK-tyr
MAPK
  22 Apr 2001: Based on MKP1 parameters. The original kinetics have been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. The only constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. The rates are treated as the same as for MKP-1, based on Chu Y, Solski PA, Khosravi-Far R, Der CJ, Kelly K. (1996) J Biol Chem. 271(11):6497-6501.
13 Enzyme Activity:
PKC-act-GEF

Enzyme Molecule:
PKC-active		66.666744explicit E-S complexinact-GEF
GEF*
  Rate constants are generic PKC rates. See Chen SJ, Klann E, Gower MC, Powell CM, Sessoms JS, Sweatt JD. (1993) Biochemistry 32(4):1032-9. This reaction activates GEF. Gives >= 2X stim of ras, and a 2X stim of MAPK over amount from direct phosph of c-raf. Note that it is a push-pull reaction, and also get effect through phosph and inact of GAPs.
14 Enzyme Activity:
PKC-act-raf

Enzyme Molecule:
PKC-active		66.666744explicit E-S complexcraf-1
craf-1*
  Rate constants are from Chen SJ, Klann E, Gower MC, Powell CM, Sessoms JS, Sweatt JD. (1993) Biochemistry 32(4):1032-1039. k3 = 4 Km for this substrate is trickier. Specific substrates are in the uM range, so we use a higher Km here. This may be too conservative in which case PKC would have a still higher effect on raf. The presence of this phosphorylation and activation step is from Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR. (1993) Nature 364(6434):249-52.
15 Enzyme Activity:
PKC-inact-GAP

Enzyme Molecule:
PKC-active		66.6667254explicit E-S complexGAP
GAP*
  Rate constants are generic PKC rates. This reaction inactivates GAP. The reaction is from Boguski MS and McCormick F (1993) Nature 366(6456):643-54. The phosphorylation Vmax is 6x higher to account for balance of GDP-Ras:GDP-Ras.
16 Enzyme Activity:
Sos.Ras_GEF

Enzyme Molecule:
Shc*.Sos.Grb2		0.50510.024explicit E-S complexGDP-Ras
GTP-Ras
  Rates are from Orita S, Kaibuchi K, Kuroda S, Shimizu K, Nakanishi H, Takai Y (1993) J Biol Chem. 268(34):25542-25546
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