Selective Inhibitors of Bacterial Phosphopantothenoylcysteine Synthetase

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Nov 12

PMID 19902973

Citations 14

Authors

James D Patrone

Jiangwei Yao

Nicole E Scott

Garry D Dotson

Affiliations

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Abstract

Bacterial phosphopantothenolycysteine synthetase (PPCS) catalyzes the formation of phosphopantothenoylcysteine (PPC) from (R)-phosphopantothenate, l-cysteine, and cytidine-5'-triphosphate (CTP) and has been shown to be essential for growth and survival. The reaction proceeds through a phosphopantothenoyl cytidylate, mixed anhydride intermediate. Both structural and kinetic characterization studies on PPCS have shown differences in the nucleobase binding site between the bacterial and human enzyme. We report for the first time the design and synthesis of mimics of the phosphopantothenoyl cytidylate, which proved to be potent inhibitors of PPCS. These compounds were evaluated in vitro against PPCS from human and several species of bacteria and showed marked selectivity (up to 1000-fold) toward the bacterial enzymes. A phosphodiester intermediate mimic was the most potent of the compounds synthesized and displayed slow-onset, tight-binding kinetics toward E. faecalis PPCS.

Citing Articles

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Targeting CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity.

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Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.

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