Histamine-N -methyltransferase

HA turnover is rapid in the brain, with a half-life of about 30 min. This can change very quickly depending on neuronal activity. There is no high-affinity uptake system for HA once released, HA is inactivated by catabolism. In the brain, released HA is methylated almost exclusively by the enzyme histamine-N-methyltransferase (E.C. 2.1.1.8). The tele-methyl-HA is subsequently degraded by monoamine oxidase-B (MAO-B) and aldehyde dehydrogenase to produce tele-methylimidazoleacetic acid (Brown et ah, 2001). 

Orr, E. Quay, W. B. (1975). Hypothalamic 24-hour rhythms in histamine, histidine, decarboxylase and histamine-N-methyltransferase. Endocrinology 96, 941-5. 

Biosynthesis is performed in one step by the enzyme L-histidine decarboxylase (HDC, E.C. 4.1.1.22). Histamine metabolism occurs mainly by two pathways. Oxidation is carried out by diamine oxidase (DAO, E.C. 1.4.3.6), leading to imidazole acetic acid (IAA), whereas methyla-tion is effected by histamine N-methyltransferase (HMT, E.C. 2.1.1.8), producing fe/e-methylhistamine (t-MH). IAA can exist as a riboside or ribotide conjugate. t-MH is further metabolized by monoamine oxidase (MAO)-B, producing fe/e-methylimidazole acetic acid (t-MIAA). Note that histamine is a substrate for DAO but not for MAO. Aldehyde intermediates, formed by the oxidation of both histamine and t-MH, are thought to be quickly oxidized to acids under normal circumstances. In the vertebrate CNS, histamine is almost exclusively methylated... 

Barnes, W. G. and Hough, L. B. Membrane-bound histamine N-methyltransferase in mouse brain possible role in the synaptic inactivation of neuronal histamine. /. Neurochem. 82 1262-1271, 2002. 

Nishibori, M., Tahara, A, Sawada, K., Sakiyama, J., Nakaya, N. and Saeki, K. Neuronal and vascular localization of histamine N-methyltransferase in the bovine central nervous system. Eur. J. Neurosci. 12 415-424,2000. 

A high intracerebral level of S-adenosylhomocysteine may inhibit methylation reactions involving S-adenosyl-methionine. The metabolic repercussions would be extensive, including deficient methylation of proteins and of phos-phatidylethanolamine as well as an inhibition of catechol-O-methyltransferase and histamine-N-methyltransferase. 

Weinshilboum, R.M., et al., "Methylation Pharmacogenetic Catechol O-Methyltrans-ferase, Thiopurine Methyltransferase, and Histamine N-Methyltransferase," Annu. Rev. Pharmacol. Toxicol., 39,19-52 (1999). 

Weinshilboum RM, Otterness DM, Szumlanski CL. Methylation pharmacogenetics catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol 1999 39 19-52. 

GLYCINE METHYLTRANSFERASE HISTAMINE N-METHYLTRANSFERASE HOMOCYSTEINE METHYLTRANSFERASE... 

HISTAMINE N-METHYLTRANSFERASE HISTIDINE AMMONIA-LYASE DEHYDROALANINE HISTIDINE DECARBOXYLASE Histidine decarboxylase reduction, BOROHYDRIDE REDUCTION HISTIDINOL DEHYDROGENASE... 

The inactivation of histamine is achieved both by enzymatic metabolism of the amine and by transport processes that reduce the concentration of the compound in the region of its receptors. Histamine metabolism occurs primarily through two pathways (Fig. 38.1). The most important of these involves histamine N-methyltransferase, which catalyzes the transfer of a... 

Histamine N-methyltransferase catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to histamine to form N-methylhistamine. This assay is suitable for following activity during enzyme purification. 

Horton JR, Sawada K, Nishibori M, Cheng X. Structural basis for inhibition of histamine N-methyltransferase by diverse dmgs. J. Mol. Biol. 2005 353 334-344. 

Preuss CV, Wood TC, Szumlanski CL, Raftogianis RB, Otterness DM, Girard B et al. Human histamine N-methyltransferase pharmacogenetics Common genetic polymorphisms that alter activity. Mol Pharmacol 1998 53 708-17. 

Sasaki Y, Ihara K, Ahmed S et al (2000) Lack of association between atopic asthma and polymorphisms of the histamine HI receptor, histamine H2 receptor, and histamine N-methyltransferase genes. Immunogenetics 51 238-240... 

Weinshilboum, R. M., Otterness, D. M., Szumlanski, C. L. Methylation pharmacogenetics catechol 0-methyltransferase, thiopu-rine methyltransferase, and histamine N-methyltransferase. Tvrmu. Rev. Pharmacol. Toxicol. 1999, 39, 19-52. 

Histamine was previously mentioned as a putative neurotransmitter (Chapter 12). It may have a role in sedation and wakefulness. In fact, drowsiness had been implicated previously with a possible inhibition of histamine-N-methyltransferase by antihistamines and subsequently with the blockade of central histaminergic receptors as well. However, it... 

Fig. 37.3. Major metabolic pathways of histamine, from intradermal histamine as measured in the urine in 12 hours in human males (5). HMT, histamine N-methyltransferase MAO-B, monoamine oxidase type B DAO, diamineoxidase ALDH, aldehyde dehydrogenase ADO, aldehyde oxidase XO, xanthine oxidase PRT, phosphoribosyl transferase.

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