DESIGN OF METABOLIC CONTROL FOR LARGE FLUX CHANGES

Metabolic Control Analysis has invalidated many traditional biochemica l concepts of control, in particular the rate-limiting step. However, it has not been used to question the mechanisms by which pathway flux is thought to be controlled, such as the action of allosteric effecter s or of covalent modification mechanisms. Here we use Control Analysis and computer simulation to examine the response of pathway segments t o change in flux imposed by action on an enzyme outside the segment. W hether these segments contain near-equilibrium enzyme-catalysed reacti ons, cooperative enzymes, feedforward activation loops or feedback inh ibition loops, their responses are significantly different from those observed in vivo. In particular, they do not exhibit the remarkable de grees of metabolite homoeostasis during large flux changes that have f requently been observed experimentally. On the other hand, near-consta nt levels of metabolites in spite of large changes of flux are consist ent with our recent proposal that multi-site modulation-simultaneous a ctivation of many pathway steps-is the normal method by which metaboli sm is controlled. (C) 1996 Academic Press Limited