| - | Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound, enzyme that catalyzes the oxidative deamination of arylalkylamine, neurotransmitters and has been a target for a number of clinically used, drug inhibitors. The 1.7-A structure of the reversible isatin-MAO-B, complex has been determined; it forms a basis for the interpretation of, the enzyme's structure when bound to either reversible or irreversible, inhibitors. 1,4-Diphenyl-2-butene is found to be a reversible MAO-B, inhibitor, which occupies both the entrance and substrate cavity space in, the enzyme. Comparison of these two structures identifies Ile-199 as a, "gate" between the two cavities. Rotation of the side chain allows for, either separation or fusion of the two cavities. Inhibition of the enzyme, with N-(2-aminoethyl)-p-chlorobenzamide results in the formation of a, covalent N(5) flavin adduct with the phenyl ring of the inhibitor, occupying a position in the catalytic site overlapping that of isatin., Inhibition of MAO-B with the clinically used, trans-2-phenylcyclopropylamine results in the formation of a covalent, C(4a) flavin adduct with an opened cyclopropyl ring and the phenyl ring in, a parallel orientation to the flavin. The peptide bond between the, flavin-substituted Cys-397 and Tyr-398 is in a cis conformation, which, allows the proper orientation of the phenolic ring of Tyr-398 in the, active site. The flavin ring exists in a twisted nonplanar conformation, which is observed in the oxidized form as well as in both the N(5) and the, C(4a) adducts. An immobile water molecule is H-bonded to Lys-296 and to, the N(5) of the flavin as observed in other flavin-dependent amine, oxidases. The active site cavities are highly apolar; however, hydrophilic, areas exist near the flavin and direct the amine moiety of the substrate, for binding and catalysis. Small conformational changes are observed on, comparison of the different inhibitor-enzyme complexes. Future MAO-B drug, design will need to consider "induced fit" contributions as an element in, ligand-enzyme interactions.
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| - | Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures., Binda C, Li M, Hubalek F, Restelli N, Edmondson DE, Mattevi A, Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9750-5. Epub 2003 Aug 11. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12913124 12913124]
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