Profiling substrate specificity of two series of phenethylamine analogs at monoamine oxidase A and B

Abstract

The membrane bound enzyme monoamine oxidase exist in two splice variants designated A and B (MAO-A and MAO-B) and are key players in the oxidative metabolism of monoamines in mammalians. Despite their importance and being a prevalent target for the development of inhibitors as drugs, no systematic study of substrate specificity has been reported. In this study we present a systematic study of the MAO-A and MAO-B substrate specificity profile by probing two series of phenethylamine analogs. Km and kcat values were determined for four N-alkyl analogs 2-5 and four aryl halide analogs 6-9 at MAO-A and MAO-B. A following in silico study disclosed a new adjacent compartment to the MAO-B substrate pocket defined by amino acids Tyr188, Tyr435, Tyr398, Thr399, Cys172 and Gly434. This new insight is important for the understanding of the substrate specificity of the MAO-B enzyme and will be relevant for future drug design within the field of monoamines.

Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B

“…11 The inhibitory activity against hMAO-B was increased by introducing bulkier and more lipophilic substituents onto position 4 of the phenyl ring, as previously reported in the literature. 37 A similar trend was also observed for the turnover of variously substituted substrates of the benzylamine and phenethylamine classes, 38 where the binding affinity improved with increasing hydrophobicity of the substituent.…”

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

“… b Constants reported by Zapata et al [ 23 ]. c Constants reported by Heuson et al [ 43 ]. d Constants reported by Kinemuchi et al [ 30 ].…”

2-Phenethylamines in Medicinal Chemistry: A Review

“…MAO A and MAO B are the two enzyme isoforms, sharing a 70% sequence identity and differentiating each other in the substrate scope [ 213 ]. Theoretical approaches to rationalize isoform selection by substrates have been described [ 214 , 215 ]. As these two oxidases are responsible for neurotransmitter inactivation by oxidation, their dysfunction drives several neurological disorders, hence the therapeutic attractiveness ( Figure 19 , Table 7 ).…”