Homoisocitrate dehydrogenase is involved in the
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-aminoadipate pathway of
l-lysine biosynthesis in higher fungi such as yeast and human pathogenic fungi. This enzyme catalyzes the oxidative decarboxylation of (2
R,3
S)-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
Ki = 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.