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pubmed:abstractText |
Homoisocitrate dehydrogenase is involved in the alpha-aminoadipate pathway of L-lysine biosynthesis in higher fungi such as yeast and human pathogenic fungi. This enzyme catalyzes the oxidative decarboxylation of (2R,3S)-homoisocitrate into 2-ketoadipate using NAD(+) as a coenzyme. A series of aza-, oxa-, and thia-analogues of homoisocitrate was designed and synthesized as an inhibitor for homoisocitrate dehydrogenase. Among them, thia-analogue showed strong competitive inhibitory activity as K(i)=97 nM toward homoisocitrate dehydrogenase derived from Saccharomyces cerevisiae. Kinetic studies suggested that the formation of the enolate intermediate played an important role in inhibition.
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pubmed:affiliation |
Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan.
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