Metabolic Interlock

Abstract

Abstract It is suggested that a regulatory superstructure of sophisticated interactions exerted between metabolic pathways acts to reinforce and modify the basic allosteric controls operating within specific pathways. Examples are cited to illustrate that small molecules may act as regulatory signals for enzymes that are located in different, apparently remote, metabolic pathways. (a) Regulatory interactions operating between the terminal branches of the biosynthetic pathway for aromatic amino acids are summarized as the simplest examples of the phenomenon. (b) Prephenate dehydratase, an enzyme of phenylalanine synthesis, was not only inhibited by phenylalanine but was also activated by either leucine or methionine. The activation was noncompetitive and independent of the competitive inhibition exerted by phenylalanine. Nutritional experiments with amino acid analogues verified the reality of these relationships in vivo. Data in vitro and in vivo lead to the conclusion that the activation of prephenate dehydratase by leucine or methionine is primarily significant under conditions of low phenylalanine (inhibitor) concentration. (c) A number of observations demonstrated regulatory influences of histidine upon the biosynthesis of tryptophan. A hypothesis is tendered which focuses upon 5-phosphoribosyl-1-pyrophosphate, a metabolite that is common to the synthesis of both tryptophan and histidine, as the key entity relating the two pathways.