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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	4	3	0

Accession and Pathway Details

Accession Name	Accession No.	Accession Type	Pathway Link
Ajay_Bhalla_ 2004_Feedback_ Tuning	78	Network	Shared_Object_Ajay_Bhalla_2004_Feedback_Tuning, PKC, PLA2, PLCbeta, Gq, MAPK, Ras, EGFR, Sos, PLC_g, CaMKII, CaM, PP1, PP2B, PKA, AC
This model is taken from Ajay SM, Bhalla US. Eur J Neurosci. 2004 Nov;20(10):2671-80. This is the feedback model from Figure 8a.

GTP-Ras acting as a Molecule in Ajay_Bhalla_2004_Feedback_Tuning Network

Name	Accession Name	Pathway Name	Initial Conc. (uM)	Volume (fL)	Buffered
GTP-Ras	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Ras Pathway No. : 353	0	1.5	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 Ajay_Bhalla_2004_Feedback_Tuning Network

Enzyme Molecule / Enzyme Activity	Accession Name	Pathway Name	Km (uM)	kcat (s^-1)	Ratio	Enzyme Type	Reagents
GAP / GAP-inact-ras	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Ras Pathway No. : 353	1.01039	10	4	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%). 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.

GTP-Ras acting as a Product of an Enzyme in Ajay_Bhalla_2004_Feedback_Tuning Network

	Enzyme Molecule / Enzyme Activity	Accession Name	Pathway Name	Km (uM)	kcat (s^-1)	Ratio	Enzyme Type	Reagents
1	GEF-Gprot-bg / GEF-bg_act-ras	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Ras Pathway No. : 353	0.505051	0.02	4	explicit E-S complex	Substrate GDP-Ras Product GTP-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
2	GEF* / GEF*-act-ras	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Ras Pathway No. : 353	0.505051	0.02	4	explicit E-S complex	Substrate GDP-Ras Product GTP-Ras
	Kinetics same as GEF-bg-act-ras
3	CaM-GEF / CaM-GEF-act-ras	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Ras Pathway No. : 353	0.505051	0.02	4	explicit E-S complex	Substrate GDP-Ras Product GTP-Ras
	Kinetics same as GEF-bg_act-ras
4	Shc*.Sos.Grb2 / Sos.Ras_GEF	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Shared_Object_ Ajay_Bhalla_ 2004_Feedback_ Tuning Pathway No. : 347	0.505051	0.02	4	explicit E-S complex	Substrate GDP-Ras Product GTP-Ras

GTP-Ras acting as a Substrate in a reaction in Ajay_Bhalla_2004_Feedback_Tuning 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-act-craf	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Shared_Object_ Ajay_Bhalla_ 2004_Feedback_ Tuning Pathway No. : 347	9.9999 (uM^-1 s^-1)	0.5 (s^-1)	Kd(bf) = 0.05(uM)	-	Substrate GTP-Ras craf-1* Product Raf*-GTP-Ras
	Assume the binding is fast and limited only by the amount of Ras* available. 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 4e-5 From Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. So we raise kb 4x to 4 This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414 May 16, 2003 Changed Ras and Raf to synaptic levels, an increase of about 2x for each. To maintain the percentage of complexed Raf, reduced the kf by 2.4 fold to 10.
2	Ras-intrinsic-GT Pase	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Ras Pathway No. : 353	0.0001 (s^-1)	0 (s^-1)	-	-	Substrate GTP-Ras Product GDP-Ras
	This is extremely slow (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 kf = 1e-4
3	Ras-act-unphosph -raf	Ajay_Bhalla_ 2004_Feedback_ Tuning Accession No. : 78	Shared_Object_ Ajay_Bhalla_ 2004_Feedback_ Tuning Pathway No. : 347	6 (uM^-1 s^-1)	1 (s^-1)	Kd(bf) = 0.1667(uM)	-	Substrate GTP-Ras craf-1 Product Raf-GTP-Ras
	18 May 2003. This reaction is here to provide basal activity for MAPK as well as the potential for direct EGF stimulus without PKC activation. Based on model from FB/fb28c.g: the model used for MKP-1 turnover. The rates there were constrained by basal activity values.

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