874156-89-5Relevant academic research and scientific papers
Phosphinate inhibitors of the D-glutamic acid-adding enzyme of peptidoglycan biosynthesis
Tanner, Martin E.,Vaganay, Sabine,Van Heijenoort, Jean,Blanot, Didier
, p. 1756 - 1760 (2007/10/03)
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.
