Metabolic Interlock

Regulatory interactions which relate small molecules and enzymes that are located in different sequences of biochemical reactions have been termed metabolic interlock. One of the simplest examples of the phenomenon occurs in the branching biochemical pathway for the synthesis of aromatic amino acids in Bacillus subtilis. Although prephenate dehydratase is not a member enzyme of the tryptophan-specific biosynthetic pathway, tryptophan inhibits the activity of prephenate dehydratase as effectively as the feedback inhibition exerted by phenylalanine. The inhibitions by tryptophan and phenylalanine are competitive with respect to prephenic acid, the substrate for the enzyme. Tyrosine, the end product of the third branch of the pathway, reverses the inhibition of prephenate dehydratase by tryptophan although it does not exhibit a strong allosteric effect alone. Several experiments showed that the allosteric specificities of prephenate dehydratase for tryptophan and tyrosine function in vivo. It was possible to show physiological conditions under which wild type cells were susceptible to growth inhibition by tryptophan. These conditions were equated with lower levels of intracellular tyrosine. More striking effects were noted by using mutant strains having a partial requirement for tyrosine. Hence, a mechanism appears to operate which decreases intracellular phenylalanine levels whenever intracellular levels of tyrosine are limiting or depleted. Methionine and leucine, allosteric activators of prephenate dehydratase, were found to reverse growth inhibition caused by tryptophan. The enzyme properties of several classes of mutants selected for resistance to growth inhibition by tryptophan are described.