Information transfer in metabolic pathways. Effects of irreversible steps in computer models

Various metabolic models have been studied by computer simulation in an effort to understand why allowing for the reversibility of the reaction catalysed by pyruvate kinase, normally considered as irreversible for all practical purposes, significantly altered the behaviour of the model of glycolysis in Trypanosoma brucei [Eisenthal, R. & Cornish-Bowden, A. (1998) J. Biol. Chem. 273, 5500-5505]. Studies of several much simpler models indicate that the enzymes catalysing early steps in a pathway must receive information about the concentrations of the metabolites at the end of the pathway if a model is to be able to reach a steady state; treating all internal steps as reversible is just one way of ensuring this. Feedback inhibition provides a much better way, and as long as feedback loops are present in a model it makes almost no difference to the behaviour whether the intermediate steps with large equilibrium constants are treated as irreversible. In the absence of feedback loops, ordinary product inhibition of all the enzymes in the chain can also transfer information; this is efficient for regulating fluxes but very inefficient for regulating intermediate concentrations. More complicated patterns of regulation, such as activation of a competing branch or forcing flux through a parallel route, can also serve to some degree as ways of passing information around an irreversible step. However, they normally do so less efficiently than inhibition, because the extent to which an enzyme or a pathway can be activated always has an upper limit (which may be below what is required), whereas most enzymes are inhibited completely at saturating concentrations of inhibitor.