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Phosphinate inhibitors of the D-glutamic acid-adding enzyme of peptidoglycan biosynthesis

TitlePhosphinate inhibitors of the D-glutamic acid-adding enzyme of peptidoglycan biosynthesis
Publication TypeJournal Article
Year of Publication1996
AuthorsTanner, ME, Vaganay, S, vanHeijenoort, J, Blanot, D
JournalJournal of Organic Chemistry
Volume61
Pagination1756-1760
Date PublishedMar
Type of ArticleArticle
ISBN Number0022-3263
Keywords(AMINOALKYL)PHOSPHINATE, ATP, D-ALANINE LIGASE, ESCHERICHIA-COLI, INACTIVATION, MECHANISM, PHOSPHINOTHRICIN, PURIFICATION, RAPID-QUENCH, SYNTHETASE
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 (IC50 = 0.68 mu 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 IC50 values of 29 mu 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.

URL<Go to ISI>://A1996TZ99700030