Title | Phosphinate inhibitors of the D-glutamic acid-adding enzyme of peptidoglycan biosynthesis |
Publication Type | Journal Article |
Year of Publication | 1996 |
Authors | Tanner, ME, Vaganay, S, vanHeijenoort, J, Blanot, D |
Journal | Journal of Organic Chemistry |
Volume | 61 |
Pagination | 1756-1760 |
Date Published | Mar |
Type of Article | Article |
ISBN Number | 0022-3263 |
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 |
![](https://chem.ubc.ca/sites/default/files/styles/header_large_c/public/header_images/ugradlab-header.jpg?itok=-FidXx5L×tamp=1585256910)