engleski

The binding of histamine and N-methylhistamine to monoamine oxidase B and their metabolic pathways

Histamine is an important mediator of many biological processes including inflammation, gastric acid secretion, neuromodulation, and regulation of immune function. Due to its potent pharmacological activity even at very low concentrations, the degradation of histamine has to be carefully regulated to avoid adverse reactions, since it can even be toxic when it is present either in excess or in the wrong metabolic context. Two major routes of histamine inactivation in mammals are: (a) methylation of the imidazole ring, catalyzed by histamine N-methyltransferase (HMT), and (b) oxidative deamination of the primary amino group, catalyzed by diamine oxidase (DAO). HMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the secondary imidazole amino group forming Nmethylhistamine, and is a highly specific enzyme that does not show significant methylation of other substrates. N-methylhistamine is not active at the histamine receptor sites, and is further metabolized by monoamine oxidase (MAO), a primary degradation enzyme for a range of biogenic and dietary amines in cells, including amine neurotransmitters in the brain, which is why it has been the central pharmacological target for treating depression and Parkinson’s disease for over 60 years. The notion that histamine is essentially not a substrate for MAO, whereas N-methylhistamine is, poses a very important question: for a promiscuous enzyme such as MAO, what is the origin of its unexpected selectivity towards two very similar compounds, yet completely identical in their reactive ethylamine chain parts.

MAO B, MM-PBSA, MD, QM

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