Inhibition of L-Kynurenine 3-Hydroxylase from Saccharomyces carlsbergensis by α-Keto Acid Derivatives of Branched Chain Amino Acids

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L-Kynurenine 3-hydroxylase [EC 1.14.1.2] was partially purified from the mitochondrial outer membrane fraction of Saccharo-myces carlsbergensis by Sephadex G-200 gel chromatography, and the effects of leucine and its related compounds on the enzyme were investi-gated. α-Keto acid derivatives of the three branched chain amino acids were found inhibitory to the partially purified kynurenine 3-hydroxylase, but branched chain amino acids were without effect. α-Ketoisocaproate (KIC), a keto acid analogue of L-leucine, inhibited kynurenine 3-hy-droxylase noncompetitively with apparent K; values of 4.2 and 8.3 mM for kynurenine and NADPH respectively. a-Ketoglutarate and pyruvate were mixed-type inhibitors of the enzyme. KIC production by S. carlsbergensis grown in medium containing no leucine was negligible, while that in leucine-supplemented medium in-creased in proportion to the amount of L-leucine incorporated into cells. From the results, it was proposed that KIC produced from leucine lowered synthesis of NAD from tryptophan by inhibiting L-kynurenine 3-hydroxylase, a possible rate-limiting enzyme in the tryptophan-NAD pathway in Saccharomyces carlsbergensis.
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