β,γ Unsaturated amino acids as irreversible enzyme inhibitors

Abstract

IRREVERSIBLE enzyme inhibitors whose mechanisms of action are based on the k_cat term rather than on K_s are highly specific. Inhibitors of this type possess hidden reactive moieties which are unmasked enzymatically. On generation, the reactive product engages in a chemical reaction with an active site residue resulting in irreversible inactivation of the enzyme. Thus, the enzyme produces its own irreversible inhibitor from a chemically unreactive substrate. Inhibitors of this type will be referred to as k_cat inhibitors, and several synthetic inhibitors of this type have been reported¹. Here I describe an example of a naturally occurring molecule which acts by this mechanism: specifically, the irreversible inhibition of soluble, pyridoxal linked, L-aspartate amino transferase by the bacterial toxin L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) isolated from Pseudomonas aeruginosa².