Nonpeptidyl amine inhibitors are substrates of lysyl oxidase.

The activity of highly purified bovine aortic lysyl oxidase against an insoluble aortic elastin substrate is inhibited by lysine, nonpeptidyl derivatives of lysine, P-aminopropionitrile (BAPN), and aliphatic monoand diamines. Inhibition requires the presence of a primary amino function. Although other stereochemical requirements for inhibition are not unusually rigid, inhibition is sensitive to the molecular distance between the w-amino group and the a carbon of diamino acid inhibitors, and is favored if the a-amino group is acetylated and the a-carboxyl group is amidated or esterified, suggesting optimal interaction with compounds resembling endopeptidyl lysine. Inhibition by lysine derivatives, n-butylamine, and BAPN exhibits competitive Lineweaver-Burk plots while inhibition with aliphatic diamines is at least partially competitive with the elastin substrate, indicating the involvement of the active site in the inhibition. Irreversible inhibition of the enzyme slowly develops upon incubation of enzyme with p-acetyl-L-lysine methyl ester, BAPN, n-butylamine, or 1,4-diaminobutane at 37°C in the absence of the elastin substrate. Lysine and its derivatives, diamines, and n-butylamine, but not BAPN, are oxidized by lysyl oxidase in the course of the timeand temperature-dependent inhibition which they induce, as evidenced by the peroxidase-coupled assay of HzOz produced from these amines by lysyl oxidase. Formation of n-butyraldehyde from n-butylamine was measured by the aldehyde dehydrogenase-coupled oxidation of nbutyraldehyde to n-butanoic acid. These studies reveal the ability of lysyl oxidase to utilize nonpeptidyl amines as substrates and indicate that these amines must be catalytically processed to irreversibly inhibit this enzyme.