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Emergent Properties of Networks of Biological Signaling Pathways Constants and Database of References Simulation Parameters
Source: Science Vol. 283: 381-387 (1999)

Michaelis-Menten equation and relationship to rate consts.

Genesis formulation:
S + E <--k2---k1--> SE ---k3---> P + E
Where S is substrate, E is enzyme, SE is enzyme complex, and P is product.

Vmax = max velocity = k3.
Derivation:
Substrate is saturating, so all of E is in SE form.
So Vmax.[Etot] = [SE].k3 == [Etot].k3

Km = (k3 + k2)/k1 (by definition)

Standard assumption in models (unless explicit information is available about rate consts)

k2 = k3 * 4
This is not entirely arbitrary. In many enzymes k2 >> k3. If k2 is small compared to k3 then a huge proportion of the enzyme will be in the complex form, assuming Km is fixed. In such cases it may be better to explicitly model the entire reaction rather than use the enzyme object. The factor of 4 keeps the amount of enz complex fairly small while avoiding extreme rate consts which might cause numerical difficulties.

Standard bimolecular reaction

 A + B <--kb---kf--> C
Where A and B are reactants and C is the product. Note that this is completely reversible. The equilibrium dissociation constt is:

Kd = kb/kf
(by definition)
So if B is limiting, and half of B is bound, then at equil
[A][Bhalf].kf = [Chalf == Bhalf].kb => [A] = kb/kf = Kd so Kd is that conc of A at which half of B is in the bound form.
And, obviously, the association or binding constt is:
Ka = kf/kb = 1/Kd

Proportion of protein to cell wt: 15% (Lehninger pg 19)

Proportion of lipid to cell wt: 2%

On average, about 50% of membrane wt is protein (up to 75% in some organelles) (Alberts et al. First ed. p 264). So maybe 2% of cell mass is membrane protein.

Volume of 'cell' in model:

1e-15 m^3 = 10 uM cube = 1e-12 liters = 1e-6 ul

- Scale factor from uM to #/cell (used extensively in model)

1 uM = 6e5 #/cell
Derivation:
Vol of cell = 1e-12 liters
so 1uM = 1e-18 moles = 6.023e5 molecules/cell

Conversion from umol/min/mg to #/sec/#:
1 min = 60 sec
1 mg = (1e-3/Mwt) * 1e6 umol
so 1 umol/min/mg = Mwt/(60 * 1e3) #/sec/# = Mwt/6e4 #/sec/#

Example Calculation of kf and kb from Kd and tau for A + B <====> C
Assume tau is 1/second
Assume Kd is 1 uM.
Then kb is approx 1/sec too.

Kd = kb/kf

so kf = kb/Kd = 1/sec * 1/(1 uM)

1 uM = 6e5 #/cell

so kf = 1/sec * 1/(6e5 #) = 1.667e-6 . 1/sec . 1/#

(The numbers would subsequently be refined using simulations to match the experiments).

 

Reaction Units

Reaction rate units are in number of reactant molecules and seconds, i.e. 1/sec for zeroth order, 1/(#.sec) for first order, and so on. This formulation is independent of volume terms and is therefore appropriate when considering interactions between compartments with different volumes.

 

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Simulation parameters: EGFR

 

A: EGFR:

1. S. H. Ryu, K. S. Cho, K.-Y Lee, P.-G. Suh, S. G. Rhee, J. Biol. Chem. 262, 12511 (1987)
2. S. Okada, K. Yamauchi, J. E. Pessin, J. Biol. Chem. 270, 20737 (1995)
3. K. K. Teng et al., J. Biol. Chem. 270, 20677 (1995)
4. S. B. Waters et al., J. Biol. Chem. 271, 18224 (1996)
5. K. Helin and L. Beguinot, J. Biol. Chem. 266, 8363 (1991)
6. Grb2/Sos interaction: Y. M. Chook, G. D. Gish, C. M. Kay, E. F. Pai, T. Pawson, J. Biol. Chem. 271, 30472 (1996).

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Simulation parameters: Ras activation

 

B: Ras:

1. CaM activation of Ras: C. L. Farnsworth et al., Nature 376, 524 (1995)
2. PKC activation of Ras: S. Orita et al., J. Biol. Chem. 268, 25542 (1993)
3. PKC activation of Ras: W. Kolch et al., Nature 364, 249 (1993)
4. E. Gulbins et al., Mol. Cell Biol. 14, 906 (1994)
5. bg activation: M. S. Boguski and F. McCormick, Nature 366, 643 (1993),
6. H. Daub, F. Ullrich Weiss, C. Wallasch, A. Ullrich, Nature 379, 557 (1996)
7. EGF activation: T. Sasaoka, W. J. Langlois, J. W. Leitner, B. Draznin, J. M. Olefsky, J. Biol. Chem. 269, 32621 (1994)
8. PKA inactivation: P. L. Hordijk, I. Verlaan, K. Jalink, E. J. van Corven, W. H. Moolenaar, J. Biol. Chem. 269, 3534 (1994)
9. B. M. T. Burgering, G. J. Pronk, P. C. van Weeren, P. Chardin, J. L. Bos, EMBO J. 12, 4211 (1993)

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Simulation parameters: Adenylyl Cyclases 1/8 and 2

 

C: AC 1/8, AC2:

J. P. Pieroni, O. Jacobowitz, J. Chen, R. Iyengar, Curr. Opin. Neurobiol. 3, 345 (1993)

O. Jacobowitz, J. Chen, R. T. Premont, R. Iyengar, J. Biol. Chem. 268, 3829 (1993)

W.-J. Tang, J. Krupinski, A. G. Gilman, J. Biol. Chem. 266, 8595 (1991)

M. Yoshimura and D. M. F. Cooper, J. Biol. Chem. 268, 4604 (1993)

K. D. Lustig, B. R. Conklin, P. Herzmark, R. Taussig, H. R. Bourne, J. Biol. Chem. 268, 13900 (1993)

PKA stimulation of PDE: C. Sette, E. Vicini, M. Conti, J. Biol. Chem. 269, 18271 (1994).

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Simulation parameters: mGluR and Gq

 

D: mGluR/Gq Gq:

S. P. Fay, R. G. Posner, W. N. Swann, L. A. Sklar, Biochem. 30, 5066 (1991)

I.-H. Pang and P. Sternweis, J. Biol. Chem. 265, 18707 (1990)

mGluR: M. Martin, J. M. Sanz, A. Cubero, FEBS Lett 316, 191 (1993)

K. Nakamura, T. Nukada, T. Haga, H. Sugiyama, J. Physiol. Lond. 474, 35 (1994)

combined: Berstein et al., J. Biol. Chem. 267, 8081 (1992).

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Simulation parameters: PLA2 and AA

 

E: PLA₂:

MAPK activation: R. A. Nemenoff et al., J. Biol. Chem. 268, 1960 (1993)

J. Wijkander and R.Sundler, Eur. J. Biochem. 202, 873 (1991)

C. C. Leslie and J. Y. Channon, Biochim. Biophys. Acta 1045, 261 (1990)

L.-L. Lin et al., Cell 72, 269 (1993)

C. C. Leslie, J. Biol. Chem. 266, 11366 (1991).

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Simulation parameters: PLC-gamma

 

F: PLCg:

M. I. Wahl, G. A. Jones, S. Nishibe, S. G. Rhee, G. Carpenter, J. Biol. Chem. 267, 10447 (1992)

S. Nishibe et al., Science 250, 1253 (1990)

C.-Y. J. Hsu, D. R. Hurwitz, M. Mervic, A. Zilberstein, J. Biol. Chem. 266, 603 (1991)

S. H. Ryu, K. S. Cho, K.-Y. Lee, P.-G Suh, S. G. Rhee, J. Biol. Chem. 262, 12511 (1987).

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Simulation parameters: PLC-beta

 

G: PLCb:

S. H. Ryu, K. S. Cho, K.-Y. Lee, P.-G Suh, S. G. Rhee, J. Biol. Chem. 262, 12511 (1987)

A. V. Smrcka, J. R. Hepler, K. O. Brown, P. C. Sternweis, Science 251, 804 (1991)

P. C. Sternweis, A. V. Smrcka, S. Gutowski, Phil. Trans. R. Soc. Lond. B. 336:1276, 35-41 (1992).

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Simulation parameters: MAPK cascade

 

H: MAPK:

Ras activation by PKC: W. Kolch et al., Nature 364, 249 (1993)

MAPKK activation by Ras: J. M. Kyriakis et al., Nature 358, 417 (1992)

MAPKK activation by Ras: T. Force et al., Proc. Natl. Acat. Sci. U.S.A. 91, 1270 (1994)

MAPK: R. Seger et al., J. Biol. Chem. 267, 14373 (1992)

MAPK: T. A. J. Haystead, P. Dent, J. Wu, C. M. M. Haystead, T. W. Sturgill, FEBS Lett. 306, 17 (1992)

MAPK: J. S. Sanghera, H. B. Paddon, S. A. Bader, S. L. Pelech, J. Biol. Chem. 265, 52 (1990)

Combined: C.-Y. F. Huang, J. E. Ferrell, Jr., Proc. Natl. Acad. Sci. U.S.A. 93, 10078 (1996).

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Simulation parameters: CaMKII

 

I: CaMKII:

P. I. Hanson, T. Meyer, L. Stryer, H. Schulman, Neuron 12, 943 (1994)

P. I. Hanson and H. Schulman, Ann. Rev. Biochem. 61, 559 (1992)

P. I. Hanson and H. Schulman, J. Biol. Chem. 267, 17216 (1992)

S. G. Miller and M. B. Kennedy, Cell 44, 861 (1986)

J. E. Lisman, Trends Neurosci. 17, 406 (1994)

J. E. Lisman and M. A. Goldring, Proc. Natl. Acad. Sci. U.S.A. 85, 5320 (1988).

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Simulation parameters: PKA

 

J: PKA:

S. O. Doskeland and D. Ogreid, J. Biol. Chem. 259, 2291 (1984)

S. O. Doskeland and D. Ogreid, Int. J. Biochem. 13, 1 (1981)

P. Hasler, J. J. Moore, G. M. Kammer, FASEB J. 6, 2735 (1992)

S. B. Smith, H. D. White, J. B. Siegel, E. G. Krebs, , Proc. Natl. Acad. Sci. U.S.A. 78, 1591 (1981).

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Simulation parameters: PKC

 

K: PKC:

Review: Y. Nishizuka, Nature 334, 661 (1988)

J. D. Schaechter and L. I. Benowitz, J. Neurosci. 13, 4361 (1993)

T. Shinomura, Y. Asaoka, M. Oka, K. Yoshida, Y. Nishizuka, Proc. Natl. Acad. Sci. U.S.A. 88, 5149 (1991)

U. Kikkawa, Y. Takai, R. Minakuchi, S. Inohara, Y. Nishizuka, J. Biol. Chem. 257, 13341 (1982).

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Simulation parameters: Calcium regulation

 

Channel Permeabilities

L: Ca:

R. N. McBurney and I. R. Neering Trends Neurosci. 10, 164 (1987)

T. Meyer and L. Stryer, Proc. Natl. Acad. Sci. U.S.A. 85, 5051 (1988)

D. A. Lauffenburger and J. J. Linderman, Receptors: models for binding, trafficking and signaling. (Oxford University Press, New York, 1993).

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Simulation parameters: CaM

 

M: CaM:

W. Drabikowski, H. Brzeska, S. Yu. Venyaminov, J. Biol. Chem. 257, 11584 (1982)

T. Meyer, P. I. Hanson, L. Stryer, H. Schulman, Science 256, 1199 (1992)

S. Forsen, H. J. Vogel, T. Drakenberg, Calcium and cell function VI, 113 (1986)

P. Stemmer and C. B. Klee, Biochemistry 33, 6859 (1994)

J. R. Slemmon and M. R. Martzen, J. Neurochem. 64, 92 (1995)

K.-P. Huang, F. L. Huang, H.-C. Chen, Arch. Biochem. Biophys. 305, 570 (1993).

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Simulation parameters: CaN/PP2B (Calcineurin)

 

N: Calcineurin (CaN, PP2B):

P. Stemmer and C. B. Klee, Biochem. 33, 6859 (1994)

M. C. Mumby and G. Walter, Physiol. Rev. 73, 673 (1993)

B. A. Perrino et al., J. Biol. Chem. 267, 15965 (1992)

K. Seki, H.-C. Chen, K.-P. Huang, Arch. Biochem. Biophys. 316, 673 (1995).

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Simulation parameters: PP1

 

O: PP1:

J. Lisman, Trends Neurosci. 17, 406 (1994)

P. Cohen, Ann. Rev. Bioch. 58, 453 (1989)

P. Stralfors, Eur. J. Biochem. 149, 295 (1985)

Y. Saitoh, H. Yamamoto, K. Fukunaga, Y. Matsukado, E. Miyamoto, J. Neuroch. 49, 1286 (1987)

J. G. Foulkes, S. J. Strada, P. J. F. Henderson, P. Cohen, Eur. J. Biochem. 132, 309 (1983).

 

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