Monoamine Oxidases: The Biochemistry of the Proteins As Targets in Medicinal Chemistry and Drug Discovery

Abstract

Monoamine oxidase (MAO, EC.1.4.3.4) has been a drug target for 60 years, with the primary rationale of developing drugs to treat neuropsychiatric disorders. The biological importance of MAO is to regulate amine levels is the brain and to metabolize amines and drugs in the periphery. This review of the biochemistry of MAO A and MAO B describes the functional properties of the two enzymes integrated with knowledge of the structures of the many MAOinhibitor complexes published in the last 10 years. The analysis of activity, and the chemical and kinetic mechanisms are discussed. Inhibition studies on human MAO in vitro are now facilitated by assays using readily available materials but the kinetics of MAO involving alternative oxidative pathways and sensitivity to the oxygen concentration mean that careful analysis of the data is required as well as the good practice of determining mechanism of inhibition and kinetic constants. Kinetic constants can then be compared with thermodynamic calculations. Inhibitors bind to both the oxidized and reduced forms of MAO present during turnover so both forms should be considered when using molecular dynamics to facilitate drug design. Interaction of inhibitors with the active site can be detected as changes in the visible spectrum and these changes can provide clues about the flavin adduct formed for irreversible inhibitors or about the proximity to the flavin for reversible inhibitors. Developing areas (knock-out mice for behavior, the imidazoline binding site, and imaging to monitor the activity and the inhibition of MAO in the patient) are mentioned.

Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine

“…15 Moreover, we have also shown that the protonation state of Lys296 does not have an effect on the hydride transfer reaction in MAO B, which is consistent with the proposed function of the lysine as stabilizing the superoxide required for the regeneration of the enzyme. In conjunction with additional experimental and computational work, the data presented here improve the understanding of mechanism of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors for antiparkinsonian and neuroprotective use …”

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…[63,64] amines occurring in food, such as tyramine. In the brain, MAO B mainly metabolises dopamine, while MAO A predominantly metabolizes serotonin, which is why these two isoforms are key pharmaceutical targets in alleviating the symptoms of Parkinson's disease and depression, respectively [87,88]. However, MAO selectivity is quite poor since, for example, MAO B also decomposes serotonin only five times slower than dopamine [89].…”

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B

“…In humans MAO A is predominantly found in adrenergic, catecholaminergic and dopaminergic neurons and deactivates serotonin, dopamine, norepinephrine and epinephrine. Human MAO B participates in dopamine degradation and is mainly expressed in serotonergic neurons and glial cells1415. Therefore, MAO inhibitors are frequently investigated for treatment of depression and Parkinson’s disease16.…”