Mechanism of the stereospecific irreversible inhibition of bacterial glutamic acid decarboxylase by (R)-(-)-4-aminohex-5-ynoic acid, an analog of 4-aminobutyric acid

Abstract

4-Aminohex-5-ynoic acid inhibits bacterial [Escherichia coli] glutamic acid decarboxylase [EC 4.1.1.15] in a time-dependent irreversible manner. The inhibition is stereospecific and requires the abstraction of the propargylic H from 4(R)-(-)-4-aminohex-5-ynoic acid. This leads to the generation of a reactive alkylating agent in the active site which can react with a nucleophilic residue. At complete inhibition, there is incorporation of 1 molecule of inhibitor/pyridoxal binding site. If the decarboxylation of glutamate occurs with retention of configuration, the irreversible inhibition of this enzyme by the 4-(R) isomer can be rationalized on the basis of reversibility of the protonation step in the normal catalytic mechanism.