Synthesis and evaluation of inhibitors for Escherichia coli carbamyl phosphate synthetase

Abstract

The design, synthesis, and evaluation of potential multisubstrate analog inhibitors for Escherichia coli carbamyl phosphate synthetase (CPS) are described. The inhibitors, which combine structural features of glutamine plus ammonia or of glutamine plus a mimic of the electrophilic ammonia acceptor, were designed to probe the spatial relationship between the substrate binding sites on the two subunits of the enzyme. Of the inhibitors described, 2-amino-3-[(N-phosphorylglycyl)amino]propanoate, 2a, with a Ki value of 60 μm, represents the most potent reversible inhibitor yet reported for E. coli CPS. The synthetic route to the inhibitors utilized a convenient protection strategy whose refinement was described previously for manipulating ω-amino- or ω-carboxyl-substituted α-amino acids (J. M. Scholtz and P. A. Bartlett, 1988, Synthesis, 542). © 1989.