Aminoalkylphosphinate inhibitors of D-Ala-D-Ala adding enzyme

摘要

Pseudo-tri- and -tetra-peptide aminoalkylphosphinic acids of general structure X-Lys-PO2H-Gly-Ala have been synthesised as transition state analogues for D-Ala-D-Ala adding enzyme, The key synthetic step used to assemble the C-terminal dipeptide unit is a modified Arbusov reaction, coupling bromopropionyl-D-alanine methyl ester to a silylated aminoalkylphosphonite. Kinetic assays with the purified E. coli enzyme reveal that the phosphinate analogues act as reversible competitive inhibitors, with K-i values in the range 200-700 mu M. Extended analogues mimicking the peptide chain of the UDPMurNAc-L-Ala-gamma-D-Glu-m-DAP substrate show increased binding affinity for the enzyme active site. These are the first reported inhibitors for D-Ala-D-Ala adding enzyme. [References: 30]