Phosphinate Inhibitors of the D-Glutamic Acid-Adding Enzyme of Peptidoglycan Biosynthesis
Document Type
Article
Publication Date
12-1-1997
Journal / Book Title
The Journal of Organic Chemistry
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 μM) 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 μM 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.
DOI
10.1021/jo951780a
Montclair State University Digital Commons Citation
Rotella, David, "Phosphinate Inhibitors of the D-Glutamic Acid-Adding Enzyme of Peptidoglycan Biosynthesis" (1997). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 564.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/564
