Title: Principles of quantitative design in metabolism. The case of moiety-supply units
Authors: Armindo Salvador, Pedro Coelho, Bharathi Pandurangan, Michael A. Savageau
Abstract:Do naturally evolved metabolite concentrations and enzyme kinetic parameters adhere to any widespread principles? We addressed this question for one of the most prevalent circuits in metabolic networks: moiety-transfer cycles (MTC), whereby a pair of coupled reactions transfers moiety from a donor (D) to an acceptor molecule (A) via a cycled intermediate (U, moiety-uncharged form, C, charged form). About 70% of the enzyme-catalyzed reactions in Escherichia coli and Saccharomyces cerevisiae participate in MTC. Most MTC play a role analogous to that of power-supply units in electronic circuits. Namely, they must reliably supply moiety at the required rate while keeping the concentration of the charged carrier fairly constant. Here, we consider cases where the sum U+C is conserved and both enzymes follow irreversible Michaelis-Menten kinetics, having the respective substrates as the only effectors that participate in the cycle. These conditions are met approximately by redox cycles that feed reducing equivalents to anabolic and antioxidant defense processes. We inferred a set of design principles that must apply so that these MTC perform as effective moiety-supply units. Namely, in the resulting basal steady state [U]/[C] must be low; the supply-side enzyme must satisfy >[U]; the demand-side enzyme must satisfy <[C] and either >[A] or >[I]. (Here, I stands for an inhibitor regulating demand.) Which of the latter alternatives should hold depends on whether demand is positively regulated by A, as is usually the case in antioxidant protection, or negatively regulated by I, as is more usual in anabolic pathways. We examined the extent to which concrete biological realizations adhere to these design principles through both detailed studies of well-characterized MTC and a broad survey of KMs and metabolite concentrations in .a coli and S. cerevisiae. We found that the biological realizations that we analyzed in detail adhere to these design principles. Furthermore, the broad survey indicates that these design principles hold pervasively across metabolic processes and organisms.
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