Thiahomoisocitrate: a highly potent inhibitor of homoisocitrate dehydrogenase involved in the alpha-aminoadipate pathway.

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.