Thiahomoisocitrate: A highly potent inhibitor of homoisocitrate dehydrogenase involved in the α-aminoadipate pathway
- 作者：Takashi Yamamoto ; Tadashi Eguchi
- 关键词：Homoisocitrate dehydrogenase ; Lysine biosynthesis ; Inhibitor ; Substrate analogue
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2008
- 期刊代码：9_09680896
- 类别：ch
- 出版时间：15 March 2008
- 卷：16
- 期：6
- 页码：3372-3376
- 文件大小：288 K
摘要
Homoisocitrate dehydrogenase is involved in the 
-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 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.
-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 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.