Inhibitors of Bacterial Cystathionine -Lyase: Leads for New Antimicrobial Agents and Probes of Enzyme Structure and F

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• 作者：Linda J. Ejim ; Jan E. Blanchard ; Kalinka P. Koteva ; Rachael Sumerfield ; Nadine H. Elowe ; Jonathan D. Chechetto ; Eric D. Brown ; Murray S. Junop ; Gerard D. Wright
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 22, 2007
• 年：2007
• 卷：50
• 期：4
• 页码：755 - 764
• 全文大小：619K
• 年卷期：v.50,no.4(February 22, 2007)
• ISSN：1520-4804

文摘

The biosynthesis of methionine is an attractive antibiotic target given its importance in protein and DNAmetabolism and its absence in mammals. We have performed a high-throughput screen of the methioninebiosynthesis enzyme cystathionine s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lyase (CBL) against a library of 50 000 small molecules and haveidentified several compounds that inhibit CBL enzyme activity in vitro. These hit molecules were of twoclasses: those that blocked CBL activity with mixed steady-state inhibition and those that covalently interactedwith the enzyme at the active site pyridoxal phosphate cofactor with slow-binding inhibition kinetics. Wedetermined the crystal structure of one of the slow-binding inhibitors in complex with CBL and used thisstructure as a guide in the synthesis of a small, focused library of analogues, some of which had improvedenzyme inhibition properties. These studies provide the first lead molecules for antimicrobial agents thattarget cystathionine s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lyase in methionine biosynthesis.