Multiplicity and ligand specificity

Two forms of the enzyme exist, MAO-A and MAO-B, that are encoded by separate genes.53 These enzymes are ~ 80% similar, and possess overlapping, albeit sometimes distinctive, substrate specificities. Serotonin, norepinephrine, and epinephrine are the major endogenous substrates for MAO-A. The indoleamine nucleus of serotonin appears in a few drug classes, notably the triptan class of antimigraine drugs. These drugs are metabolized by MAO-A via pathways that ultimately generate carboxylic acid metabolites.40 The acetylenic compound, clorgyline, is a selective mechanism-based inhibitor of MAO-A, and reversible inhibitors of the enzyme are under development as antidepressant drugs. Amongst the neurotransmitters, dopamine is selectively metabolized by MAO-B. Another acetylenic compound, deprenyl, is a selective mechanism-based inhibitor of MAO-B and the levo enantiomer, selegiline, is marketed as Eldepryl and used as an adjunct to l-DOPA in Parkinsonism. The rationale here is to minimize metabolism of dopamine and reduce the dose of l-DOPA required therapeutically. MAO-B is also implicated in the bioactivation of the environmental neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).54

5.07.2.3.2 Structure

Human MAO-A and MAO-B are FAD-containing flavoproteins containing 527 and 520 amino acids (~63kDa), respectively. Models for the membrane topography of MAO suggests that it is monotopically localized in, and anchored to, the mitochondrial membrane by a hydrophobic C-terminus. In contrast to the FMOs, MAOs have their prosthetic group linked covalently to a cysteine residue located in the C-terminal half of the protein. Both human forms of the enzyme have been crystallized, revealing differences in the volume of the active site activity, 550 and 700 A3, for human MAO-A and MAO-B, respectively.55 The ligand specificity of the two enzymes is controlled, in part, by a tyrosine (MAO-B) to isoleucine (MAO-A) change in the C-terminal half of the protein.56

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