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.
Yamamoto
Takashi
T
Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan.
Eguchi
Tadashi
T
D015074:2-Aminoadipic Acid / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D014233:Tricarboxylic Acids / Q000737:chemistry / Q000494:pharmacology*
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D014233:Tricarboxylic Acids; C517550:homoisocitric acid; D015074:2-Aminoadipic Acid; D000429:Alcohol Oxidoreductases; C021368:homoisocitrate dehydrogenase