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Accession Type:
Network
Differential syn
thesis of mRNA
Shared Object_
Differential syn
thesis of mRNA
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 Enzyme
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Enzyme List for pathway Shared Object_Differential synthesis of mRNA (Pathway Number 1115)

 Molecule Name/
Site Name 		Km (uM) kcat (1/s)Ratio
(k2/k3)		Enzyme TypeSubstrate Product
1 Enzyme Activity:
braf_dash_GTP_
dash_Ras1

Enzyme Molecule:
braf_dash_GTP_
dash_Ras		0.160.24explicit E-S complexMAPKK
MAPKK_dash_ser
 
2 Enzyme Activity:
braf_dash_GTP_
dash_Ras2

Enzyme Molecule:
braf_dash_GTP_
dash_Ras		0.160.24explicit E-S complexMAPKK_dash_ser
MAPKK_star
 
3 Enzyme Activity:
braf_dash_rap1_
dash_GTP1

Enzyme Molecule:
bRaf_Rap1GTP		0.160.34explicit E-S complexMAPKK
MAPKK_dash_ser
 
4 Enzyme Activity:
braf_dash_Rap1_
dash_GTP2

Enzyme Molecule:
bRaf_Rap1GTP		0.160.34explicit E-S complexMAPKK_dash_ser
MAPKK_star
 
5 Enzyme Activity:
CaM.PDE1

Enzyme Molecule:
CaM.PDE1		39.6825104explicit E-S complexcAMP
cAMP
 
6 Enzyme Activity:
CaMKIVdephos

Enzyme Molecule:
PP2A		8.800224explicit E-S complex
  • pCaMKIV_CaM_Ca_
    c
    		• CaMKIV_CaM_Ca_c
     
    7 Enzyme Activity:
    CaMKIVphosph

    Enzyme Molecule:
    CaMKK_CaM_Ca_c    		1.31.14explicit E-S complexCaMKIV_CaM_Ca_c
  • pCaMKIV_CaM_Ca_
    c
    •  
    8 Enzyme Activity:
    CaMKKdephosph

    Enzyme Molecule:
    PP2A    		4.99990.74explicit E-S complexCaMKKp
    		CaMKK_c
     
    9 Enzyme Activity:
    CaMKKphosph

    Enzyme Molecule:
    PKA_dash_active    		4.69990.68333.99997073156explicit E-S complexCaMKK_CaM_Ca_c
    		CaM_dash_Ca4
    CaMKKp
     
    10 Enzyme Activity:
    CaM_dash_GEF_
    dash_act_dash_
    ras

    Enzyme Molecule:
    CaM_dash_GEF    		0.50510.024explicit E-S complexGDP_dash_Ras
    		GTP_dash_Ras
      Kinetics same as GEF-bg_act-ras
    11 Enzyme Activity:
    CaN_dephos_
    TORC1

    Enzyme Molecule:
    CaM_Ca_n_dash_
    CaNAB    		0.40.14explicit E-S complexpTORC1
    		TORC1c
     
    12 Enzyme Activity:
    Cbl_phospho

    Enzyme Molecule:
    Src_star    		0.5404explicit E-S complexCbl
    		Cbl_star
     
    13 Enzyme Activity:
    craf_dash_deph

    Enzyme Molecule:
    PPhosphatase2A    		15.656864explicit E-S complex
  • craf_dash_1_
    star
    		• craf_dash_1
      See parent PPhosphatase2A for parms
    14 Enzyme Activity:
    craf_star_star_
    dash_deph

    Enzyme Molecule:
    PPhosphatase2A    		15.656864explicit E-S complex
  • craf_dash_1_
    star_star
  • craf_dash_1_
    star
    •   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.
    15 Enzyme Activity:
    dephosph_dash_
    PP1_dash_I_star

    Enzyme Molecule:
    CaM_Ca_n_dash_
    CaNAB    		4.97080.344explicit E-S complex
  • PP1_dash_I1_
    star
    		• PP1_dash_I1
     
    16 Enzyme Activity:
    dephosph_inhib1

    Enzyme Molecule:
    CaM_Ca_n_dash_
    CaNAB    		4.97080.344explicit E-S complexI1_star
    		I1
     
    17 Enzyme Activity:
    dephosph_
    inhib1_noCaM

    Enzyme Molecule:
    CaNAB_dash_Ca4    		4.97080.0344explicit E-S complexI1_star
    		I1
      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
    18 Enzyme Activity:
    dephosp_S6K

    Enzyme Molecule:
    PP2A    		8.800514explicit E-S complexactive_RSK2
    		ppRSK
     
    19 Enzyme Activity:
    dephos_S6K

    Enzyme Molecule:
    PP2A    		8.800514explicit E-S complexpRSK
    		RSK
     
    20 Enzyme Activity:
    GAP_dash_inact_
    dash_ras

    Enzyme Molecule:
    GAP    		1.0104104explicit E-S complexGTP_dash_Ras
    		GDP_dash_Ras
      From Eccleston et al JBC 268(36)pp27012-19 get Kd < 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.
    21 Enzyme Activity:
    GEF_dash_bg_
    act_dash_ras

    Enzyme Molecule:
    GEF_dash_Gprot_
    dash_bg    		0.50510.024explicit E-S complexGDP_dash_Ras
    		GTP_dash_Ras
      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
    22 Enzyme Activity:
    GEF_star_dash_
    act_dash_ras

    Enzyme Molecule:
    GEF_star    		0.50510.024explicit E-S complexGDP_dash_Ras
    		GTP_dash_Ras
      Kinetics same as GEF-bg-act-ras
    23 Enzyme Activity:
    kenz

    Enzyme Molecule:
    AC1_dash_CaM    		20184explicit E-S complexATP
    		cAMP
     
    24 Enzyme Activity:
    kenz

    Enzyme Molecule:
    AC2_star    		20.114974explicit E-S complexATP
    		cAMP
     
    25 Enzyme Activity:
    MAPKKthr

    Enzyme Molecule:
    MAPKK_star    		0.04630.34explicit E-S complexMAPK_dash_tyr
    		MAPK_star
      Rate consts same as for MAPKKtyr.
    26 Enzyme Activity:
    MAPKKtyr

    Enzyme Molecule:
    MAPKK_star    		0.04630.34explicit E-S complexMAPK
    		MAPK_dash_tyr
      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
    27 Enzyme Activity:
    MAPKK_dash_deph

    Enzyme Molecule:
    PPhosphatase2A    		15.656864explicit E-S complexMAPKK_star
    		MAPKK_dash_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.
    28 Enzyme Activity:
    MAPKK_dash_
    deph_dash_ser

    Enzyme Molecule:
    PPhosphatase2A    		15.656864explicit E-S complexMAPKK_dash_ser
    		MAPKK
     
    29 Enzyme Activity:
    MAPK_star_dash_
    feedback

    Enzyme Molecule:
    MAPK_star    		25.641104explicit E-S complex
  • craf_dash_1_
    star
  • craf_dash_1_
    star_star
    •   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.
    30 Enzyme Activity:
    MKP1_dash_thr_
    dash_deph

    Enzyme Molecule:
    MKP_dash_1    		0.133344explicit E-S complexMAPK_star
    		MAPK_dash_tyr
      See MKP1-tyr-deph
    31 Enzyme Activity:
    MKP1_dash_tyr_
    dash_deph

    Enzyme Molecule:
    MKP_dash_1    		0.133344explicit E-S complexMAPK_dash_tyr
    		MAPK
      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
    32 Enzyme Activity:
    PDE

    Enzyme Molecule:
    cAMP_dash_PDE    		19.8413104explicit E-S complexcAMP
    		cAMP
     
    33 Enzyme Activity:
    PDE1

    Enzyme Molecule:
    PDE1    		39.71.6674.00119976005explicit E-S complexcAMP
    		cAMP
     
    34 Enzyme Activity:
    PDE_star

    Enzyme Molecule:
    cAMP_dash_PDE_
    star    		19.8413204explicit E-S complexcAMP
    		cAMP
     
    35 Enzyme Activity:
    phospho_S6K

    Enzyme Molecule:
    MAPK_star    		5.29991.74explicit E-S complexRSK
    		pRSK
     
    36 Enzyme Activity:
    phosph_dash_AC2

    Enzyme Molecule:
    PKC_dash_active    		33.333344explicit E-S complexAC2
    		AC2_star
     
    37 Enzyme Activity:
    phosph_dash_PDE

    Enzyme Molecule:
    PKA_dash_active    		7.594explicit E-S complexcAMP_dash_PDE
  • cAMP_dash_PDE_
    star
    •  
    38 Enzyme Activity:
    phosph_Sos

    Enzyme Molecule:
    MAPK_star    		2.56104explicit E-S complexSos
    		Sos_star
     
    39 Enzyme Activity:
    PKA_dash_
    phosph_dash_GEF

    Enzyme Molecule:
    PKA_dash_active    		7.594explicit E-S complexinact_dash_GEF
  • inact_dash_GEF_
    star
    •   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
    40 Enzyme Activity:
    PKA_dash_
    phosph_dash_I1

    Enzyme Molecule:
    PKA_dash_active    		7.594explicit E-S complexI1
    		I1_star
      #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.
    41 Enzyme Activity:
    PKC_dash_act_
    dash_GEF

    Enzyme Molecule:
    PKC_dash_active    		3.333344explicit E-S complexinact_dash_GEF
    		GEF_star
      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
    42 Enzyme Activity:
    PKC_dash_act_
    dash_raf

    Enzyme Molecule:
    PKC_dash_active    		66.66844explicit E-S complexcraf_dash_1
  • craf_dash_1_
    star
    •  
    43 Enzyme Activity:
    PKC_dash_inact_
    dash_GAP

    Enzyme Molecule:
    PKC_dash_active    		3.333344explicit E-S complexGAP
    		GAP_star
      Rate consts copied from PCK-act-raf This reaction inactivates GAP. The idea is from the Boguski and McCormick review.
    44 Enzyme Activity:
    PLC_g_phospho

    Enzyme Molecule:
    BDNF_TrkB2_
    star_clx    		0.30.54explicit E-S complexPLC_g
    		PLC_g_star
     
    45 Enzyme Activity:
    PLC_g_phospho

    Enzyme Molecule:
    PLCg_basal    		0.30.54explicit E-S complexPLC_g
    		PLC_g_star
     
    46 Enzyme Activity:
    PP2A_dash_
    dephosph_dash_
    I1

    Enzyme Molecule:
    PP2A    		7.828364.16666666667explicit E-S complexI1_star
    		I1
      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
    47 Enzyme Activity:
    PP2A_dash_
    dephosph_dash_
    PP1_dash_I_star

    Enzyme Molecule:
    PP2A    		7.828364.16666666667explicit E-S complex
  • PP1_dash_I1_
    star
    		• PP1_dash_I1
      k1 changed from 3.3e-6 to 6.6e-6
    48 Enzyme Activity:
    Raf_dash_GTP_
    dash_Ras.1

    Enzyme Molecule:
    Raf_dash_GTP_
    dash_Ras    		0.15910.34explicit E-S complexMAPKK
    		MAPKK_dash_ser
      Kinetics are the same as for the craf_1* activity, ie., k1=5.5e-6, k2=0.42, k3 = 0.105 These are basedo n Force et al PNAS USA 91 1270-1274, 1994., but k1 is scaled up 5x (ie., Km is scaled down 5x to the value used here and for craf_1* activity: Km = 0.1591).
    49 Enzyme Activity:
    Raf_dash_GTP_
    dash_Ras.2

    Enzyme Molecule:
    Raf_dash_GTP_
    dash_Ras    		0.15910.34explicit E-S complexMAPKK_dash_ser
    		MAPKK_star
      Kinetics are the same as for the craf_1* activity, ie., k1=5.5e-6, k2=0.42, k3 = 0.105 These are basedo n Force et al PNAS USA 91 1270-1274, 1994., but k1 is scaled up 5x (ie., Km is scaled down 5x to the value used here and for craf_1* activity: Km = 0.1591).
    50 Enzyme Activity:
    Raf_star_dash_
    GTP_dash_Ras.1

    Enzyme Molecule:
    Raf_star_dash_
    GTP_dash_Ras    		0.15910.34explicit E-S complexMAPKK
    		MAPKK_dash_ser
      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
    51 Enzyme Activity:
    Raf_star_dash_
    GTP_dash_Ras.2

    Enzyme Molecule:
    Raf_star_dash_
    GTP_dash_Ras    		0.15910.34explicit E-S complexMAPKK_dash_ser
    		MAPKK_star
      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
    52 Enzyme Activity:
    RapGAP1

    Enzyme Molecule:
    Rap1GAP    		12100explicit E-S complexRap1GTP
    		Rap1GDP
     
    53 Enzyme Activity:
    RapGAP2

    Enzyme Molecule:
    Rap1GAP    		12100explicit E-S complexbRaf_Rap1GTP
    		Rap1GDP
    bRaf
     
    54 Enzyme Activity:
    RAP_GEF

    Enzyme Molecule:
    CRK_C3G_Cbl_
    star_clx    		0.010.24explicit E-S complexRap1GDP
    		Rap1GTP
     
    55 Enzyme Activity:
    S6K_phospho

    Enzyme Molecule:
    PDK1    		1014explicit E-S complexppRSK
    		active_RSK2
     
    56 Enzyme Activity:
    Shc_phospho

    Enzyme Molecule:
    BDNF_TrkB2_
    star_clx    		0.83330.34explicit E-S complexShc
    		Shc_star
     
    57 Enzyme Activity:
    SIK2_phosp

    Enzyme Molecule:
    PKA_dash_active    		4.59970.14explicit E-S complexSIK2
    		SIK2_star
     
    58 Enzyme Activity:
    Sos.Ras_GEF

    Enzyme Molecule:
    Shc_
    star.Sos.Grb2    		0.05050.24explicit E-S complexGDP_dash_Ras
    		GTP_dash_Ras
     
    59 Enzyme Activity:
    Src_phospho

    Enzyme Molecule:
    PKA_dash_active    		0.05204explicit E-S complexSrc
    		Src_star
     
    60 Enzyme Activity:
    TORC1_phso_enz

    Enzyme Molecule:
    SIK2    		40.44explicit E-S complexTORC1c
    		pTORC1
     


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