Mechanism of inactivation of mammalian L-histidine decarboxylase by (S)-alpha-fluoromethylhistidine.

The mechanism of inactivation by (S)-alpha-fluoromethylhistidine (FMH) of L-histidine decarboxylase (HDC, L-histidine carboxy-lyase, EC 4.1.1.22) purified from whole bodies of fetal rats was studied. FMH inhibited the activities of HDC purified from fetal HDC as well as HDCs from the brain and stomach of adult rats. The activity was not restored by extensive dialysis, indicating that the inhibition was irreversible. The inactivation of HDC was time and concentration dependent and followed pseudo first-order kinetics. L-Histidine, a substrate, protected HDC against inactivation, but D-histidine did not. Apo-HDC was not inactivated by FMH. On labeling of HDC with [3H]FMH, a correlation was found between the extent of incorporation of radioactivity into the enzyme and the degree of inactivation. Two moles of the inhibitor were incorporated into one mole of HDC (108,000 daltons). Experiments with [carboxyl-14C]FMH and [ring 2-14C]FMH showed that decarboxylation was necessary for the inactivation and that one molecule of FMH moiety was incorporated into an HDC monomer during every three decarboxylations of FMH.