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spinqualitylabelsall models Crystal Structure of Human Monoamine Oxidase A with Harmine Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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spinqualitylabelsall models ABCB1: 3.4 Å resolution Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

IntroductionIntroduction

(MAO-A) is an oxidoreductase flavoenzyme, encoded in the MAOA gene on the X chromosome; the enzyme is present throughout the brain, central nervous system, and stomach. Two isoforms of this enzyme (MAO-A and MAO-B) are expressed on the outer surface of the mitochondrial membrane, and both are responsible for the oxidative deamination of various neurotransmitters and dietary amines [1]. Each isoform is characterized by its unique substrate specificity and inhibitor sensitivity. For example, MAO-A (found primarily in catecholaminergic neurons) preferentially oxidizes 5-hydroxytryptamine (5-HT), epinephrine, and norepinephrine; while MAO-B (found primarily in sertonergic neurons) prefers phenylethylamine and benzylamine. Both of these enzymes oxidize dopamine, tyramine, and N,N-dimethyltryptamine as well as their respective unique substrates according to the following reaction:

                   RCH2NHR' + H2O + O2 --> RCHO + R'NH2 + H2O2

in which the H₂O₂ is enzymatically removed by glutathione reductase and glutathione peroxidase to produce a reduced glutathione since heightened levels of H₂O₂ promote apoptosis signalling within cells [2]. Due to the important role MAOs play in controlling the prevalence of various neurotransmitters in the body as well as producing reactive oxygen species (ROS), an imbalance of these enzymes may be detrimental to human health.

The secondary structure, illustrated in the protein image to the right, in conjunction with the color key, below, indicates the directionality of the .

Amino Terminus

Carboxy Terminus

StructureStructure

Unlike its related dimers, human MAO-B and rat MAO-A, human MAO-A is a monomer composed of 527 amino acids, with a molecular weight of 60,512±6 Da. The first 497 amino acids in the polypeptide exist in the cytoplasm of the cell; while amino acids 498—518 are involved in an α-helix that anchors the enzyme to the mitochondrial membrane (this can clearly be seen in the provided crystal structure as the only α-helix that significantly sticks out away from the rest of the globular structure). Furthermore, amino acids 519—527 are present in the intermembrane of the mitochondria [3]. The active site of MAO-A is a single hydrophobic pocket, lined with 11 aliphatic and 5 aromatic residues, with a volume of approximately 550 cubic Å [4]. Moreover, the active site of human MAO-A is completely unique due to a loop-like conformation of residues 210-216, this is thought to be the result of interactions taking place across the monomer, which allow for the development of inhibitors specific to human MAO-A [5]. There are two crucial differences in the active sites of human MAO-A and -B, these include residues Phe-208 (Ile-199 in human MAO B) and Ile-335 (Tyr-326 in human hMAO B) [6]. The enzyme shares 70% of its amino acid sequence with human MAO-B, and the amino acids interacting with the FAD binding site in both isoforms is conserved,; therefore it is believed that the FAD binding sites are quite similar in both proteins [7]. Bach et al (1988) showed that the FAD is covalently bound to cysteine residues in both human MAO-A and -B, on Cys397 and Cys406, respectively [8].

Structural highlightsStructural highlights

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