Effect of 4-Azaleucine upon Leucine Metabolism in Salmonella typhimurium

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Abstract
Dl-4-Azaleucine (5 × 3−3m) added to exponentially growing cells of Salmonella typhimurium resulted in an abrupt cessation of growth lasting 4 to 8 hr followed by a resumption of division. The transitory nature of inhibition was not due to the instability or modification of the analogue or to a derepression of leucine-forming enzymes. Of many compounds tested, leucine served most efficiently to reverse 4-azaleucine-induced inhibition. Inhibition of growth can be explained by the fact that 4-azaleucine inhibits α-isopropylmalate synthase, the first enzyme unique to leucine biosynthesis. The analogue was a poor inhibitor of both the transamination of α-ketoisocaproate to leucine and the charging of leucine to transfer ribonucleic acid. With a leucine auxotroph starved for leucine, the analogue was incorporated into protein specifically in place of leucine. Such incorporation was accompanied by the death of almost all of the cells.