AMINOALKYLPHOSPHINATE INHIBITORS OF D-ALA-D-ALA ADDING ENZYME

Pseudo-tri- and -tetra-peptide aminoalkylphosphinic acids of general s tructure X-Lys-PO2H-Gly-Ala have been synthesised as transition state analogues for D-Ala-D-Ala adding enzyme, The key synthetic step used t o assemble the C-terminal dipeptide unit is a modified Arbusov reactio n, coupling bromopropionyl-D-alanine methyl ester to a silylated amino alkylphosphonite. Kinetic assays with the purified E. coli enzyme reve al that the phosphinate analogues act as reversible competitive inhibi tors, with K-i values in the range 200-700 mu M. Extended analogues mi micking the peptide chain of the UDPMurNAc-L-Ala-gamma-D-Glu-m-DAP sub strate show increased binding affinity for the enzyme active site. The se are the first reported inhibitors for D-Ala-D-Ala adding enzyme.