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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 as	Molecule	Sum total of	Enzyme	Substrate of an enzyme	Product of an enzyme	Substrate in Reaction	Product in Reaction
No. of occurrences	1	0	0	1	2	3	0

Accession and Pathway Details

Accession Name	Accession No.	Accession Type	Pathway Link
MAPK-bistability -fig1c	35	Network	Shared_Object_MAPK-bistability-fig1c,  Sos,  PKC,   MAPK,  PLA2,  Ras,   PDGFR
Model for figure 1c in Bhalla US et al. Science (2002) 297(5583):1018-23. The demo for this figure is available here. This synaptic signaling model is without the MKP-1 feedback, so it is bistable and remains so over long periods.

GTP-Ras acting as a Molecule in  MAPK-bistability-fig1c Network

Name	Accession Name	Pathway Name	Initial Conc. (uM)	Volume (fL)	Buffered
GTP-Ras	MAPK-bistability -fig1c Accession No. : 35	Ras Pathway No. : 184	0	1000	No
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  MAPK-bistability-fig1c Network

Enzyme Molecule / Enzyme Activity	Accession Name	Pathway Name	Km (uM)	kcat (s^-1)	Ratio	Enzyme Type	Reagents
GAP  / GAP-inact-ras	MAPK-bistability -fig1c Accession No. : 35	Ras Pathway No. : 184	1.0104	10	100	explicit E-S complex	Substrate 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  MAPK-bistability-fig1c Network

	Enzyme Molecule / Enzyme Activity	Accession Name	Pathway Name	Km (uM)	kcat (s^-1)	Ratio	Enzyme Type	Reagents
1	Shc*.Sos.Grb2  / Sos.Ras_GEF	MAPK-bistability -fig1c Accession No. : 35	Shared_Object_ MAPK-bistability -fig1c Pathway No. : 179	0.505051	0.02	4	explicit E-S complex	Substrate GDP-Ras Product GTP-Ras
	Rates from Orita et al JBC 268(34):25542-25546
2	GEF*  / GEF*-act-ras	MAPK-bistability -fig1c Accession No. : 35	Ras Pathway No. : 184	0.505051	0.02	4	explicit E-S complex	Substrate 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  MAPK-bistability-fig1c 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.

	Name	Accession Name	Pathway Name	Kf	Kb	Kd	tau	Reagents
1	Ras-intrinsic-GT Pase	MAPK-bistability -fig1c Accession No. : 35	Ras Pathway No. : 184	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.
2	Ras-act-craf	MAPK-bistability -fig1c Accession No. : 35	Shared_Object_ MAPK-bistability -fig1c Pathway No. : 179	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
3	Ras-act-unphosph -raf	MAPK-bistability -fig1c Accession No. : 35	Shared_Object_ MAPK-bistability -fig1c Pathway No. : 179	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.