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Molecule Parameter List for GTP_dash_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_dash_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	4	0

Accession and Pathway Details

Accession Name	Accession No.	Accession Type	Pathway Link
mRNA synthesis	94	Network	kinetics,  compartment_1,  compartment_2
The model consists of three major pathways: Calcium-calmodulin dependent protein kinase IV (CaMKIV), Mitogen-activated protein kinase (MAPK) and Protein Phosphatase 1 (PP1). Each of these converged on CREB activation. We also modeled further interactions with Transducer of regulated CREB activity 1 (TORC1) and the protein kinase A (PKA) pathway.

GTP_dash_Ras acting as a Molecule in  mRNA synthesis Network

Name	Accession Name	Pathway Name	Initial Conc. (uM)	Volume (fL)	Buffered
GTP_dash_Ras	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	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_dash_Ras acting as a Substrate for an Enzyme in  mRNA synthesis Network

Enzyme Molecule / Enzyme Activity	Accession Name	Pathway Name	Km (uM)	kcat (s^-1)	Ratio	Enzyme Type	Reagents
GAP  / GAP_dash_inact_ dash_ras	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	1.0104	10	4	explicit E-S complex	Substrate GTP_dash_Ras Product 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.

GTP_dash_Ras acting as a Product of an Enzyme in  mRNA synthesis Network

	Enzyme Molecule / Enzyme Activity	Accession Name	Pathway Name	Km (uM)	kcat (s^-1)	Ratio	Enzyme Type	Reagents
1	GEF_dash_Gprot_ dash_bg  / GEF_dash_bg_ act_dash_ras	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	0.5051	0.02	4	explicit E-S complex	Substrate GDP_dash_Ras Product 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
2	CaM_dash_GEF  / CaM_dash_GEF_ dash_act_dash_ ras	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	0.5051	0.02	4	explicit E-S complex	Substrate GDP_dash_Ras Product GTP_dash_Ras
	Kinetics same as GEF-bg_act-ras
3	GEF_star  / GEF_star_dash_ act_dash_ras	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	0.5051	0.02	4	explicit E-S complex	Substrate GDP_dash_Ras Product GTP_dash_Ras
	Kinetics same as GEF-bg-act-ras
4	Shc_ star.Sos.Grb2  / Sos.Ras_GEF	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	0.0505	0.2	4	explicit E-S complex	Substrate GDP_dash_Ras Product GTP_dash_Ras

GTP_dash_Ras acting as a Substrate in a reaction in  mRNA synthesis 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_dash_act_ dash_unphosph_ dash_raf	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	6 (uM^-1 s^-1)	1 (s^-1)	Kd(bf) = 0.1667(uM)	-	Substrate GTP_dash_Ras craf_dash_1 Product Raf_dash_GTP_ dash_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.
2	Ras_dash_act_ dash_craf	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	9.9996 (uM^-1 s^-1)	0.5 (s^-1)	Kd(bf) = 0.05(uM)	-	Substrate GTP_dash_Ras craf_dash_1_ star Product Raf_star_dash_ GTP_dash_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.
3	Ras_dash_act_ dash_braf	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	60 (uM^-1 s^-1)	0.5 (s^-1)	Kd(bf) = 0.0083(uM)	-	Substrate GTP_dash_Ras bRaf Product braf_dash_GTP_ dash_Ras
4	Ras_dash_ intrinsic_dash_ GTPase	mRNA synthesis Accession No. : 94	kinetics Pathway No. : 1112	0.0001 (s^-1)	0 (s^-1)	-	-	Substrate GTP_dash_Ras Product GDP_dash_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