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Accession Type:
Network
Synaptic_
Network
Shared_Object_
Synaptic_
Network
 Molecule
 Enzyme
 Reaction
PKC
PLA2
PLCbeta
Gq
MAPK
Ras
EGFR
Sos
PLC_g
CaMKII
CaM
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PP2B
PKA
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CaRegulation

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Enzyme List for pathway Shared_Object_Synaptic_Network (Pathway Number 70)

 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 et al JBC 269(22) pp 15756-15761 1994 show 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:
Deph-thr286

Enzyme Molecule:
PP1-active		5.099070.354explicit E-S complex
  • CaMKII-thr286*-C
    aM
    		• CaMKII-CaM
      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. This gives the final Km of 5.1, and Vmax of 0.35/sec.
    4 Enzyme Activity:
    Deph-thr286c

    Enzyme Molecule:
    PP1-active    		5.099070.354explicit E-S complexCaMKII***
    		CaMK-thr306
      Dephosphorylation kinetics are assumed to be the same for all phosphorylation sites on CaMKII. 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. This gives the final Km of 5.1, and Vmax of 0.35/sec.
    5 Enzyme Activity:
    Deph-thr305

    Enzyme Molecule:
    PP1-active    		5.099070.354explicit E-S complexCaMKII***
    		CaMKII-thr286
      Dephosphorylation kinetics are assumed to be the same for all phosphorylation sites on CaMKII. 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. This gives the final Km of 5.1, and Vmax of 0.35/sec.
    6 Enzyme Activity:
    Deph-thr306

    Enzyme Molecule:
    PP1-active    		5.099070.354explicit E-S complexCaMK-thr306
    		CaMKII
      Dephosphorylation kinetics are assumed to be the same for all phosphorylation sites on CaMKII. 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. This gives the final Km of 5.1, and Vmax of 0.35/sec.
    7 Enzyme Activity:
    dephosph-PP1-I*

    Enzyme Molecule:
    CaM(Ca)n-CaNAB    		4.970760.344explicit E-S complexPP1-I1*
    		PP1-I1
      Liu and Storm JBC 1989 264(22):12800-12804 say Km ~ 5 uM, Vmax = 256 nmol/min/mg ~ 0.34/sec
    8 Enzyme Activity:
    dephosph_inhib1

    Enzyme Molecule:
    CaM(Ca)n-CaNAB    		4.970760.344explicit E-S complexI1*
    		I1
      Assume the rates are the same when dephosphorylating I1 either when it is floating freely, or when it is bound to PP1 catalytic subunit. This is from Liu and Storm 1989 264(22):12800-12804
    9 Enzyme Activity:
    dephosph_
    inhib1_noCaM

    Enzyme Molecule:
    CaNAB-Ca4    		4.970760.0344explicit E-S complexI1*
    		I1
      The rates here are so slow I do not know if we should even bother with this enzyme reaction. These numbers are from Liu and Storm JBC 1989 264(22):12800-12804 They say that the CaM-free form of CaN operates at about the same Km of 5 uM, but at a much lower Vmax of 1 nmol/min/mg. Other estimates of activity without CaM suggest 10% activity, which is what I use here.
    10 Enzyme Activity:
    dephosph_
    neurogranin

    Enzyme Molecule:
    CaM(Ca)n-CaNAB    		10.0120.673.98507explicit E-S complexneurogranin*
    		neurogranin
      From Seki et al ABB 316(2):673-679
    11 Enzyme Activity:
    Deph_thr286b

    Enzyme Molecule:
    PP1-active    		5.099070.354explicit E-S complexCaMKII-thr286
    		CaMKII
      Rates are assumed to be the same for all phosphorylation sites on CaMKII. 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. This gives the final Km of 5.1, and Vmax of 0.35/sec.
    12 Enzyme Activity:
    MAPK*

    Enzyme Molecule:
    MAPK*    		25.641204explicit E-S complexPLA2-cytosolic
    		PLA2*
      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. Numbers are from Sanghera et al JBC 265 pp 52 , 1990. From Nemenoff et al 1993 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 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.
    13 Enzyme Activity:
    MAPK*-feedback

    Enzyme Molecule:
    MAPK*    		25.641104explicit E-S complexcraf-1*
    		craf-1**
      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.
    14 Enzyme Activity:
    MAPKK-deph

    Enzyme Molecule:
    PPhosphatase2A    		15.656664.16667explicit E-S complexMAPKK*
    		MAPKK-ser
      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.
    15 Enzyme Activity:
    MAPKK-deph-ser

    Enzyme Molecule:
    PPhosphatase2A    		15.656664.16667explicit E-S complexMAPKK-ser
    		MAPKK
      See parent PPhostphatase2A description for rate details
    16 Enzyme Activity:
    MKP1-thr-deph

    Enzyme Molecule:
    MKP-1    		0.066666714explicit E-S complexMAPK*
    		MAPK-tyr
      See MKP1-tyr-deph
    17 Enzyme Activity:
    MKP1-tyr-deph

    Enzyme Molecule:
    MKP-1    		0.066666714explicit E-S complexMAPK-tyr
    		MAPK
      The original kinetics from Bhalla and Iyengar Science 1999 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 et al 1993 PNAS 90:5292-5296 and Charles et al Oncogene 7:187-190 Effective Km : 67 nM kcat = 1.43 umol/min/mg
    18 Enzyme Activity:
    phosph-AC2

    Enzyme Molecule:
    PKC-active    		33.333344explicit E-S complexAC2
    		AC2*
      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
    19 Enzyme Activity:
    phosph-PDE

    Enzyme Molecule:
    PKA-active    		7.594explicit E-S complexcAMP-PDE
    		cAMP-PDE*
      Same rates as PKA-phosph-I1
    20 Enzyme Activity:
    phosph_Sos

    Enzyme Molecule:
    MAPK*    		2.5641104explicit E-S complexSos
    		Sos*
      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.
    21 Enzyme Activity:
    PKA-phosph-GEF

    Enzyme Molecule:
    PKA-active    		7.594explicit E-S complexinact-GEF
    		inact-GEF*
      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
    22 Enzyme Activity:
    PKA-phosph-I1

    Enzyme Molecule:
    PKA-active    		7.594explicit E-S complexI1
    		I1*
      Numbers 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 since Cohen et al FEBS Lett 76:182-86 1977 say rate =30% PKA act on phosphokinase beta.
    23 Enzyme Activity:
    PKC-act-GEF

    Enzyme Molecule:
    PKC-active    		3.3333344explicit E-S complexinact-GEF
    		GEF*
      Rate constants are generic PKC rates. See Chen et al 1993 Biochem 32:1032 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.
    24 Enzyme Activity:
    PKC-act-raf

    Enzyme Molecule:
    PKC-active    		66.666744explicit E-S complexcraf-1
    		craf-1*
      Rate consts from Chen et al Biochem 32, 1032 (1993) 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 et al 1993 Nature 364:249
    25 Enzyme Activity:
    PKC-inact-GAP

    Enzyme Molecule:
    PKC-active    		3.3333344explicit E-S complexGAP
    		GAP*
      Rate consts are PKC generic rates. This reaction inactivates GAP. The reaction is from the Boguski and McCormick 1993 review in Nature 366:643-654 The phosphorylation Vmax is 6x higher to account for balance of GDP-Ras:GDP-Ras.
    26 Enzyme Activity:
    PKC-phosph-neuro
    granin

    Enzyme Molecule:
    PKC-active    		28.62750.584.03448explicit E-S complexneurogranin
    		neurogranin*
      Rates from Huang et al ABB 305:2 570-580 1993
    27 Enzyme Activity:
    PKC-phosph-ng-Ca
    M

    Enzyme Molecule:
    PKC-active    		28.59480.354explicit E-S complexneurogranin-CaM
    		CaM
    neurogranin*
      Rates are 60% those of PKC-phosph-neurogranin. See Huang et al ABB 305:2 570-580 1993
    28 Enzyme Activity:
    PP2A-dephosph-I1

    Enzyme Molecule:
    PP2A    		7.8282864.16667explicit E-S complexI1*
    		I1
      PP2A does most of the dephosph of I1 at basal Ca levels. See the review by Cohen in Ann Rev Biochem 1989 58:453-508 I use a Km twice that for the preferred substrates of PP2A.
    29 Enzyme Activity:
    PP2A-dephosph-PP
    1-I*

    Enzyme Molecule:
    PP2A    		7.8282864.16667explicit E-S complexPP1-I1*
    		PP1-I1
      PP2A does most of the dephosph of I1 at basal Ca levels. See the review by Cohen in Ann Rev Biochem 1989 58:453-508 I use a Km twice that for the preferred substrates of PP2A. Here I assume that the dephosph of the PP1-bound form of I1* will proceed at the same rate as the unbound I1*.
    30 Enzyme Activity:
    Sos.Ras_GEF

    Enzyme Molecule:
    Shc*.Sos.Grb2    		0.5050510.024explicit E-S complexGDP-Ras
    		GTP-Ras
      Rates from Orita et al JBC 268(34):25542-25546


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