Me. Tanner et al., PHOSPHINATE INHIBITORS OF THE D-GLUTAMIC ACID-ADDING ENZYME OF PEPTIDOGLYCAN BIOSYNTHESIS, Journal of organic chemistry, 61(5), 1996, pp. 1756-1760
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 an
tibiotic design. Phosphinic acid 3 is a dipeptide analog linked to uri
dine diphosphate by a hydrophobic spacer. It is a good inhibitor of th
e enzyme (IC50 = 0.68 mu M) as it closely resembles the tetrahedral in
termediate 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 en
zyme with IC50 values of 29 mu M and > 1 mM, respectively. Preincubati
on of the enzyme in the presence of inhibitor 3 and ATP does not resul
t in irreversible inhibition or in the formation of a slowly decomplex
ing species, suggesting that the phosphinic acid is not phosphorylated
in the active site.