Regulation of branched-chain amino acid biosynthesis

Formation of branched-chain amino acids in microorganisms is controlled mainly by end-product inhibition of the enzyme action but also by repression of enzyme synthesis. The two mechanisms may be interrelated. Regulation of the metabolite flow by end-product inhibition is realized by the inhibition of threonine deaminase by isoleucine; inhibition of acetohydroxy acid synthetase by valine and inhibition of alpha-isopropylmalate synthetase by leucine. Acetohydroxy acid synthetase has a key position in the pathway, since the enzyme catalyzes not only the synthesis of acetolactate, the valine and isoleucine precursor from pyruvate, but also that of acetohydroxybutyrate, the isoleucine precursar from alpha-ketobutyrate and pyruvate. Quenching of valine pathway by valine would be expected to be accompanied by a quenching of the isoleucine pathway as well. Nevertheless, aceto-hydroxybutyrate is formed rather than acetolactate, since alpha-ketobutyrate has a greater affinity to the enzyme than pyruvate and the inhibitory effect of valine is directly proportional to substrate concentration. It could completely reverse the inhibition. Regulation on the physiological level of the pathways to the branched-chain amino acids occurs by the repression of the leucine and isoleucine-valine biosynthetic enzymes. A phenotypic derepression caused by valine was detectable in the case of the latter biosynthetic enzymes. The idea that aminoacyl tRNA formation is a necessary reaction in the formation of the 'repressor" has been supported by numerous data. Indeed, some of the latest reports suggest that aminoacyl tRNA interaction with feedback sensitive enzyme may play an important role in the repression.