A new method for assembling metabolic networks, with application to the Krebs citric acid cycle.

To understand why a molecular network has a particular connectivity one can generate an ensemble of alternative networks, all of which meet the same performance criteria as the real network. We have generated alternatives to the Krebs cycle, allowing group transfers and B(12)-mediated shifts that were excluded in previous work. Our algorithm does not use a reaction list, but determines the reactants and products in generic reactions. It generates networks in order of increasing number of reaction steps. We find that alternatives to the Krebs cycle are very likely to be cycles. Many of the alternatives produce toxic or unstable compounds and use group transfer reactions, which have unfavorable consequences. Although alternatives are better than the Krebs cycle in some respects, the Krebs cycle has the most favorable combination of traits.

[1]  R Heinrich,et al.  Kinetic and thermodynamic principles determining the structural design of ATP-producing systems , 1998, Bulletin of mathematical biology.

[2]  Mittenthal Je,et al.  An algorithm to assemble pathways from processes. , 1997 .

[3]  Peter H. Sellers,et al.  Mechanistic study of chemical reaction systems , 1990 .

[4]  G. Brown,et al.  Total cell protein concentration as an evolutionary constraint on the metabolic control distribution in cells. , 1991, Journal of theoretical biology.

[5]  A. Ian Scott,et al.  How Nature Synthesizes Vitamin B12 ? A Survey of the Last Four Billion Years , 1993 .

[6]  B. Clarke,et al.  Designing metabolism: Alternative connectivities for the pentose phosphate pathway , 1998 .

[7]  W. Stein,et al.  Thinking About Biology , 1993 .

[8]  G. Stephanopoulos,et al.  Computer‐aided synthesis of biochemical pathways , 1990, Biotechnology and bioengineering.

[9]  R Heinrich,et al.  Theoretical approaches to the evolutionary optimization of glycolysis: thermodynamic and kinetic constraints. , 1997, European journal of biochemistry.

[10]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[11]  Jack E. Baldwin,et al.  The evolution of metabolic cycles , 1981, Nature.

[12]  David S. Latchman,et al.  Biochemistry (4th edn) , 1995 .

[13]  J. C. Nuño,et al.  The structural design of glycolysis: an evolutionary approach. , 1999, Biochemical Society transactions.

[14]  J E Mittenthal.  An algorithm to assemble pathways from processes. , 1997, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[15]  G. Wächtershäuser,et al.  Evolution of the first metabolic cycles. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Harold J. Morowitz,et al.  A theory of biochemical organization, metabolic pathways, and evolution , 1999, Complex..

[17]  J. C. Nuño,et al.  Network organization of cell metabolism: monosaccharide interconversion. , 1997, The Biochemical journal.

[18]  H. Gest.  Evolutionary roots of the citric acid cycle in prokaryotes. , 1987, Biochemical Society symposium.

[19]  E. Meléndez-Hevia,et al.  The game of the pentose phosphate cycle: a mathematical approach to study the optimization in design of metabolic pathways during evolution. , 1990, Biomedica biochimica acta.

[20]  F. Montero,et al.  Optimization of Metabolism: The Evolution of Metabolic Pathways Toward Simplicity Through the Game of the Pentose Phosphate Cycle , 1994 .

[21]  C. Lehmann,et al.  Chemie der α-Aminonitrile 1. Mitteilung Einleitung und Wege zu Uroporphyrinogen-octanitrilen , 1987 .

[22]  J. C. Nuño,et al.  Optimal stoichiometric designs of ATP-producing systems as determined by an evolutionary algorithm. , 1999, Journal of theoretical biology.

[23]  Reinhart Heinrich,et al.  Theoretical approaches to the evolutionary optimization of glycolysis--chemical analysis. , 1997, European journal of biochemistry.

[24]  George Oster,et al.  Chemical reaction networks , 1974, Applications of Polynomial Systems.