Lysyl oxidase has emerged as an important enzyme in cancer metastasis. Its activity has been reported to become upregulated in several types of cancer, and blocking its activity has been shown to limit the metastatic potential of various cancers. The small-molecules phenylhydrazine and β-aminopropionitrile are known to inhibit lysyl oxidase; however, issues of stability, toxicity, and poorly defined mechanisms limit their potential use in medical applications. The experiments presented herein evaluate three other families of hydrazine-derived compounds – hydrazides, alkyl hydrazines, and semicarbazides – as irreversible inhibitors of lysyl oxidase including determining the kinetic parameters and comparing the inhibition selectivities for lysyl oxidase against the topaquinone-containing diamine oxidase from lentil seedlings. The results suggest that the hydrazide group may be a useful core functionality that can be developed into potent and selective inhibitors of lysyl oxidase and eventually find application in cancer metastasis research.
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 KI and kinact 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 identify the nucleophilic side chain responsible for the inhibition. The results are interpreted in terms of a computational model structure obtained by molecular modeling. Supported in part by Nuclea Biotechnologies.
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