Mechanism-based inhibitors of monoamine oxidase

Abstract

Through the study of mechanism-based inhibitors, it has been shown that the two-electron oxidation of biogenic amines carried out by the flavin moiety of monoamine oxidase occurs by stepwise electron transfer. This is illustrated by cyclopropylamine-based inhibitors. Mechanisms of propargylamine- and hydrazine-type inhibitors have also been clarified.

Enzymes react with substrates and inhibitors by forming either fleeting or stabilized adducts linked by bonds ranging from covalent to minimally attracting forces. Apoenzymes and/or cofactors may be involved in such reactions. Biochemists have approached the study of these interactions from an opportunistic point of view. An inorganic ion or a well-understood organic coenzyme will offer the most detailed chance of following the course of enzymic reactions. The macromolecular apoenzyme determines the course of interaction with substrate or inhibitor molecules of average size. Reactive portions of the participating amino acid side chains are thought to offer a handle in pinpointing reaction mechanisms while the backbone of the apoenzyme can be relegated to the background. Thiol groups of cysteine residues, serine and tyrosine phenolic hydroxyls, imino positions of indole and imidazole sections, the carboxyl of glutamic acid and amino and guanidino groups of lysine and arginine side chains have been called upon most frequently for this purpose.