title: 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.
authors.affiliation: Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Egon
authors.initials: E
authors.lastname: Heuson
authors.forename: Morten
authors.initials: M
authors.lastname: Storgaard
authors.forename: Tri H V
authors.initials: TH
authors.lastname: Huynh
authors.forename: Franck
authors.initials: F
authors.lastname: Charmantray
authors.forename: Thierry
authors.initials: T
authors.lastname: Gefflaut
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D006801:Humans; D007700:Kinetics; D007735:Kynuramine / Q000737:chemistry; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D012996:Solutions; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D011994:Recombinant Proteins; D012996:Solutions; D007735:Kynuramine; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human