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J Org Chem. 1996 Mar 8;61(5):1756-1760.

Phosphinate Inhibitors of the D-Glutamic Acid-Adding Enzyme of Peptidoglycan Biosynthesis.

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1
Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z1, Canada and URA 1131 du CNRS, Université de Paris-Sud, 91405 Orsay, France.

Abstract

We report the synthesis and initial evaluation of the first effective inhibitors of the D-glutamic acid-adding enzyme (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase or MurD). This enzyme plays a key role in bacterial peptidoglycan biosynthesis and is therefore a target for antibiotic design. Phosphinic acid 3 is a dipeptide analog linked to uridine diphosphate by a hydrophobic spacer. It is a good inhibitor of the enzyme (IC(50) = 0.68 &mgr;M) as it closely resembles the tetrahedral intermediate that is presumed to form in the ligation reaction. Compound 4 lacks the terminal UMP group, and compound 5 lacks both the linker and UDP functionalities. These are less effective inhibitors of the enzyme with IC(50) values of 29 &mgr;M and >1 mM, respectively. Preincubation of the enzyme in the presence of inhibitor 3 and ATP does not result in irreversible inhibition or in the formation of a slowly decomplexing species, suggesting that the phosphinic acid is not phosphorylated in the active site.

PMID:
11667046
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