Sandbox WWC2

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IntroductionIntroduction

Monoamine oxidase A (MAO-A) is an oxidoreductase flavoenzyme, encoded by 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-B being the other) are expressed on the outer surface of the mitochondrial membrane, and both are responsible for the oxidative deamination of various monoamine neurotransmitters and dietary amines [2]. 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 serotonergic 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 [3]. 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 polypeptide chain.

Amino Terminus

Carboxy Terminus

StructureStructure

Unlike its related dimers, human MAO-B and rat MAO-A, human MAO-A is a monomer. 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 . MAO-A composed of 527 amino acids, with a molecular weight of approximately 60.5 kDa. 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 space of the mitochondria [4].

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 [5]. 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 [6]. 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) . 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 [7].

FunctionFunction

As previously stated, the function of MAO-A is to deaminate 5-hydroxytryptamine (5-HT), epinephrine, norepinephrine, dopamine, tyramine, and N,N-dimethyltryptamine (DMT). When neurons release neurotransmitters into the synaptic cleft to bind to a receptor, some of the neurotransmitters do not bind to the receptor and are not reabsorbed. The monoamine oxidase enzymes are responsible for oxidizing some of these "free" neurotransmitters in an attempt to prevent their binding to unintended receptors, potentially causing deleterious side effects; they are also responsible for maintaining a steady state of certain neurotransmitters. Although MAO-A is found concentrated in catecholaminergic neurons, it is primarily found in the digestive system, while MAO-B is found more abundantly in the brain. There are two prevalent polymorphisms of the human MAOA gene, these include the low activity form (MAOA-L), which produces a smaller amount of the enzyme, and high activity form (MAOA-H), which results in the production of high levels of MAO-A [8]. Recent studies have found that individuals with the MAOA-L gene tend to display slightly higher levels of aggression than individuals with the MAOA-H gene (especially in the case of high-provocation situations). [9]

Due to this association between aggression and MAO-A polymorphisms, the human MAOA gene has been dubbed the "warrior gene".

DiseaseDisease

Due to the important role MAO-A plays in maintaining a balance of various neurotransmitters in the digestive and central nervous system, as well as its production of ROS, an imbalance of MAO-A may result in any of several diseases. For example, postpartum depression is a moderate to severe form of depression that occurs as the result of an excess of MAO-A in the brain that some women experience after childbirth [10]. In research conducted by Julia Sacher of the Max Planck Institute for Human Cognitive and Brain Sciences, it was concluded that the levels of MAO-A in women with postpartum depression are about 40% greater than those of average women. [11]

”Positron-Emission-Tomography (PET) of a depressive patient without medication (left) with elevated monoamine-oxidase-A-levels (green, yellow, red) and after a six-week-treatment with the monoamine-oxidase-A-inhibitor moclobemid (right)” [1]

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Brunner's syndrome (BRUNS) is a disease associated with a mutation in the MAOA gene that results in a deficiency of MAO-A and as a result causes mild intellectual disability and aggressive behavior in males. Female heterzygotes for this mutation exhibit no mental retardation or aggressive behavior [12]. Many other diseases and disorders are associated with mutations in the MAOA gene, such as: Alzheimer's disease, bipolar affective disorder, antisocial behavior, major depressive disorder, and ADHD.

Inhibition and ResearchInhibition and Research

Monoamine oxidase inhibitors (MAOIs) are among the most effective anti-depressants available, however, many of these inhibit MAO-A alongside the target MAO-B, which results in the need to be on a very strict diet while on MAOIs. This is because MAO-A is responsible for oxidizing tyramine, a monoamine found in many different foods and drinks, has been found to have a strong effect on blood pressure. Due to MAO-As effect on blood pressure and digestion those whom are prescribed MAOIs often have to follow a strict diet to prevent side effects such as dizziness, nausea, drowsiness, low blood pressure, and insomnia from occuring. The diet requires that the patient avoid: alcohol, aged cheeses, cured meats, sauerkraut, tofu, fava beans, dried fruit, fermented soy products, and fish or meat refrigerated more than 24 hours [13]. Due to the affect MAOIs have on neurotransmitters and digestive enzymes they are rarely used as an antidepressant today, even though they are very effective when prescribed to individuals in which other anti-depressants have not worked. A newer form of MAOI that has just recently come on the market, Selegiline, works by inhibiting primarily MAO-B as opposed to MAO-A; highly limiting the likeliness of side effects that are influenced by the excessive breakdown of tyramine. Isoform specific inhibitors are certainly a target for future research into treating MAO influenced disorders; particularly in child and adlolescent psychiatry [14].