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Molecule Parameter List for GTP-Ras

The statistics table lists the distribution of a molecule acting either as a substrate, product, enzyme or as a molecule within the network.
The text color of a molecule is highlighted by color.
Statistics
GTP-Ras participated asMoleculeSum total ofEnzymeSubstrate of an enzymeProduct of an enzymeSubstrate in ReactionProduct in Reaction
No. of occurrences1001230

Accession and Pathway Details
Accession NameAccession No.Accession TypePathway Link
  • mkp1_feedback_
    effects
  • 4Network
    Shared_Object_mkp1_feedback_effects Sos PKC 
    MAPK PLA2 Ras 
    PDGFR 
    This is a network involving the MAPK-PKC feedback loop with input from the PDGFR in the synapse. The distinctive feature of this model is that it includes MKP-1 induction by MAPK, and the consequent inhibitory regulation of MAPK and the feedback loop. Lots of interesting dynamics arise from this. This link provides supplementary material for the paper Bhalla US et al. Science (2002) 297(5583):1018-23. In the form of several example simulations and demos for the figures in the paper.

    GTP-Ras acting as a Molecule in  
    mkp1_feedback_effects Network
    NameAccession NamePathway NameInitial Conc.
    (uM)
    Volume
    (fL)
    Buffered
    GTP-Ras
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Ras
    Pathway No. : 37
    01000No
    Only a very small fraction (7% unstim, 15% stim) of ras is GTP-bound. Gibbs et al JBC 265(33) 20437

    GTP-Ras acting as a Substrate for an Enzyme in  
    mkp1_feedback_effects Network
    Enzyme Molecule /
    Enzyme Activity
    Accession NamePathway NameKm (uM)kcat (s^-1)RatioEnzyme TypeReagents
    GAP  /
    GAP-inact-ras
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Ras
    Pathway No. : 37
    1.010410100explicit E-S complexSubstrate
    GTP-Ras

    Product
    GDP-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%). The two sets of values are reasonably close. k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting) This is one of the rare cases where we have direct info on the k3 being rate-limiting. Hence the ratio I use for the k2:k3 rates is 100 rather than the usual 4.

    GTP-Ras acting as a Product of an Enzyme in  
    mkp1_feedback_effects Network
     Enzyme Molecule /
    Enzyme Activity
    Accession NamePathway NameKm (uM)kcat (s^-1)RatioEnzyme TypeReagents
    1Shc*.Sos.Grb2  /
    Sos.Ras_GEF
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Shared_Object_
    mkp1_feedback_
    effects

    Pathway No. : 32
  • 0.5050510.024explicit E-S complexSubstrate
    GDP-Ras

    Product
    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
    2GEF*  /
    GEF*-act-ras
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Ras
    Pathway No. : 37
    0.5050510.024explicit E-S complexSubstrate
    GDP-Ras

    Product
    GTP-Ras
        Kinetics from Orita et al JBC 268(34):25542-25546. Note that the Vmax is slow, but it does match the slow GTP hydrolysis rates.

    GTP-Ras acting as a Substrate in a reaction in  
    mkp1_feedback_effects Network
    Kd is calculated only for second order reactions, like nA+nB <->nC or nA<->nC+nD, where n is number and A,B,C,D are molecules, where as for first order reactions Keq is calculated. Kd for higher order reaction are not consider.
     NameAccession NamePathway NameKfKbKdtauReagents
    1Ras-act-craf
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Shared_Object_
    mkp1_feedback_
    effects

    Pathway No. : 32
  • 60
    (uM^-1 s^-1)
    0.5
    (s^-1)
    Kd(bf) = 0.0083(uM)-Substrate
    GTP-Ras
    craf-1*

    Product
    Raf*-GTP-Ras
      Assume binding is fast and limited only by available Ras*. 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 about 1e-4, giving a Kf of 60 for Kb of 0.5 and a tau of approx 2 sec. Based on: Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414. Also see Koide et al 1993 PNAS USA 90(18):8683-8686
    2
  • Ras-intrinsic-GT
    Pase
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Ras
    Pathway No. : 37
    0.0001
    (s^-1)
    0
    (s^-1)
    --Substrate
    GTP-Ras

    Product
    GDP-Ras
      This is extremely slow (kf = 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 There is no back reaction as we assume this to be a regular irreversible Michaelis-Menten zeroth order hydrolysis.
    3
  • Ras-act-unphosph
    -raf
  • mkp1_feedback_
    effects

    Accession No. : 4
  • Shared_Object_
    mkp1_feedback_
    effects

    Pathway No. : 32
  • 6
    (uM^-1 s^-1)
    1
    (s^-1)
    Kd(bf) = 0.1667(uM)-Substrate
    GTP-Ras
    craf-1

    Product
    RGR
      Based on rates of Ras-act-craf which has Kf=60, Kb= 0.5. This reaction was introduced to account for the PKC-independent activation of MAPK. This reac should have less affinity but similar tau as compared to the Ras-cat-craf, since the phosphorylated Raf form has a greater effect on MAPK.



    Database compilation and code copyright (C) 2022, Upinder S. Bhalla and NCBS/TIFR
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