engleski

Computational modeling of histamine metabolism in humans

Histamine is a mediator of many different important processes such as contraction of smooth muscle tissues and gastric acid secretion. It is also engaged in neurotransmission and immunomodulation. Because of its important roles, insufficient histamine degradation may cause adverse effects. There are two pathways of histamine degradation, diamine oxidase (DAO) catalyze direct oxidative deamination of histamine to imidazole acetaldehyde.[1, 2] In the other, histamine N-methyltransferase catalyzes the transfer of a methyl group to the secondary amino group of the imidazole ring forming N-methylhistamine. This compound is further metabolized by monoamine oxidase B (MAO B) forming N-methyl-imidazole acetaldehyde. In this work, we combined molecular dynamics simulations, [3] quantum mechanical cluster calculations[3] and EVB simulations to elucidate the catalytic mechanism of MAO B and DAO catalyzed oxidative deamination of N-methylhistamine and histamine. Our results suggest that the in vivo degradation of histamine to yield an imine always occurs via the same catalytic mechanism, namely direct hydride transfer from histamine and N-methylhistamine to the corresponding cofactor (TPQ or FAD, respectively), regardless of the histamine catabolic pathway. [1] T. Bieganski, J. Kusche, K. D. Feussner, R. Hesterberg, H. Richter, W. Lorenz, Arch. Immunol. Ther. Exp. 28, (1980) 901. [2] T. Bieganski, J. Kusche, K. D. Feussner, R. Hesterberg, H. Richter, W. Lorenz, Agents Actions, 10, (1980) 108. [3] A. Marsavelski, R. Vianello, Chem-Eur J. 23, (2017) 2915.

Histamine ; MAO B ; DAO ; EVB simulations

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