Irreversible Inhibitors of Bovine Aortic Lysyl Oxidase

TL;DRAbstract

Lysyl oxidase (LOX) is a copper‐containing amine oxidase with a unique lysyl tyrosyl quinone (LTQ) cofactor formed by post‐translational modification of Tyr‐187 followed by a cross‐linking reaction with the Lys‐152 side chain. The enzyme is irreversibly inhibited by hydrazines, hydrazides and semicarbazides and by β‐aminopropionitrile, βAPN. While hydrazines are known to inhibit by forming an irreversible adduct on the LTQ, the mechanism of inhibition of βAPN is known to be a mechanism‐based inhibitor although the exact site of inhibition has never been determined. We report the results of kinetic and mass spectrometric studies of the reaction of LOX with several irreversible inhibitors, including βAPN. Alkyl and aryl hydrazines were studied and K I and k inact parameters compared to determine how the nature of the organic group affects inhibition with, in general, aryl hydrazines being better inhibitors than alkyl hydrazines. The site of βAPN inhibition was investigated by LC/MS/MS to

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