Molecular Pharmacology, Vol 4, 337-348, Copyright © 1968 by the American Society for Pharmacology and Experimental Therapeutics

Mechanism of Histidine Decarboxylase Inhibition by NSD-1055 and Related Hydroxylamines

¹ Biochemistry Section, McNeil Laboratories, Inc., Fort Washington, Pennsylvania 19034

The kinetics of inhibition by 4-bromo-3-hydroxybenzyloxyamine and several other O-substituted hydroxylamines were studied using partially purified histidine decarboxylase. Hydroxylamine and O-substituted derivatives were competitive inhibitors with respect to the substrate. This type of inhibition was ascribed to competition of the oxyamino group of the inhibitor and the amino group of the substrate for a carbonyl site of the holoenzyme. Interaction of O-substituted hydroxylamines and pyridoxal phosphate, leading to the formation of oximes, was observed by following characteristic changes in absorbance and fluorescence spectra of pyridoxal phosphate oximes. Several such oximes were prepared and shown to be effective competitive inhibitors with respect to the coenzyme. Two such oximes, lacking the phosphate ester group, were substantially less inhibitory than their analogs containing the phosphate ester group.

Note:
ACKNOWLEDGMENTS The author gratefully acknowledges numerous discussions with and suggestions from members of the Chemistry Department, especially Dr. Harold Almond and Dr. Brian Reynolds, Nitrogen analyses were carried out by Mrs. Mary Christie. The expert help of Mr. Gerald Lightkep in providing rat fetus is appreciated.