|, HMT, HNMT-S1, HNMT-S2, MRT51, histamine N-methyltransferase, Histamine N-methyltransferase|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
Histamine N-methyltransferase (HNMT, HMT) is an enzyme involved in the metabolism of histamine. It is one of two enzymes involved in the metabolism of histamine in mammals, the other being diamine oxidase (DAO). HNMT catalyzes the methylation of histamine in the presence of S-adenosylmethionine (SAM-e) forming N-methylhistamine. The HNMT enzyme is present in most body tissues but is not present in serum. Histamine N-methyltransferase is encoded by a single gene, HNMT, which in humans has been mapped to chromosome 2.
The function of the HNMT enzyme is histamine metabolism by ways of Nτ-methylation using SAM-e as the methyl donor, producing N-methylhistamine, which, unless excreted, can be further processed by monoamine oxidase B (MAOB) or by DAO. Methylated histamine metabolites are excreted with urine.
In mammals, histamine is metabolized by two major pathways: oxidative deamination via DAO, encoded by the AOC1 gene, and Nτ-methylation via HNMT, encoded by the HNMT gene. In brain of mammals histamine neurotransmitter activity is controlled by Nτ-methylation since DAO is not present in the central nervous system.
The HNMT enzyme resides in the cytosol intracellular fluid. Whereas DAO metabolizes extracellular free histamine, be it either exogenous came with food or mostly endogenous released from granules of mast cells and basophils as a result of allergic reactions, in view of the fact that DAO is mainly expressed in the cells of intestinal epithelium, HNMT is involved in metabolism of the persistently present intracellular primarily endogenous histamine, mainly in kidneys and liver, but also in bronchi, large intestine, ovary, prostate, spinal cord, spleen, trachea and peripheral tissues. In the case of flawed HNMT activity, the organs which are most affected are brain, liver and mucous membrane of bronchus. Consequently, flawed HNMT activity leads to chronic forms of histamine intolerance. For instance, the main symptoms of histamine intolerance within the nervous system are anxiety, dizziness, fatigue, insomnia, myoclonic twitching and unrest. Overall, the symptoms of flawed HNMT activity are typical of symptoms of histamine intolerance, including allergic rhinitis, urticaria (hives), and peptic ulcer disease.
Whereas DAO comes to the blood stream from the organs where it is expressed (small bowel and large intestine ascendens, kidney, etc.) in a continuous manner and stored in plasma membrane-associated vesicular structures in epithelial cells, and therefore serum DAO activity can be reliably measured while diagnosing histamine intolerance, measurement of intracellular HNMT which presents primarily in the cells of the internal organs, like the liver, is troublesome, so diagnosis is done, as a rule, indirectly, through testing for genetic variants. Although the consequences of flawed DAO activity are often periodic, the consequences of flawed HNMT activity occur immediately, and the symptoms also immediately appear, for example, after meals.
The most studied genetic variant is T allele at rs11558538 (C314T, Thr105Ile), a loss-of-function allele reducing HNMT activity and associated with diseases, typical for histamine intolerance, such as asthma, allergic rhinitis and atopic eczema (atopic dermatitis). Therefore the owners of this variant should avoid intake of HNMT inhibitors which hamper enzyme activity, and also should avoid intake of histamine liberators which release histamine from granules of mast cells and basophils. In a study of 48 adults, median enzyme activity was significantly lower in subjects with the CT or TT genotype than in those with the wild-type CC genotype (485 versus 631 U/mL of red blood cells). In another study of 195 subjects, the C314T variant also showed an association with serum Interleukin-8 (IL-8) levels — individuals with the CT or TT genotype had lower levels of IL-8 (1.2 ± 0.7 versus 2.1) and higher levels of histamine (107.0 ± 53.9 versus 85.6 ± 45.7 ng/mL) in comparison with individuals with the CC genotype. The carriers of CT and TT genotypes were merged in one group in this study because there were too few participants with TT to form a group large enough to make statistical relevance, therefore CT and TT might have different enzyme activity which is not yet studied as of 2020[update]. This effect may indicate that there may be a link between this genetic variant and inflammation. Although the relationship between histamine and IL-8 has not been fully studied as of 2020[update], it is known that histamine can increase the expression of IL-8 through H1 receptors in vitro and enhance the release of IL-8 in different cell types.
Other genetic variants have been also identified to affect enzyme function. The rs1050891 (A939G, 3′-UTR) variant leads to increased enzymatic activity (messenger RNA stability), while rs758252808 (G179A, Gly60Asp) and rs745756308 (T632C, Leu208Pro) lead to decreased enzymatic activity.
The following substances are known to be HNMT inhibitors: amodiaquine, chloroquine, dimaprit, etoprine, metoprine, quinacrine, SKF91488, tacrine and diphenhydramine. HNMT inhibitors may increase histamine levels in peripheral tissues and exacerbate histamine-related diseases, such as allergic rhinitis, urticaria, and peptic ulcer disease. However, the effect of HNMT inhibitors on brain function is not yet fully understood. Some studies suggest that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.
- GRCh38: Ensembl release 89: ENSG00000150540 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000026986 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Brown DD, Tomchick R, Axelrod J (November 1959). "The distribution and properties of a histamine-methylating enzyme" (PDF). The Journal of Biological Chemistry. 234 (11): 2948–2950. PMID 13804910.
- "Entrez Gene: Histamine N-methyltransferase".
- Yoshikawa T, Nakamura T, Yanai K (February 2019). "N-Methyltransferase in the Brain". International Journal of Molecular Sciences. 20 (3): 737. doi:10.3390/ijms20030737. PMC 6386932. PMID 30744146.
- Borriello F, Iannone R, Marone G (2017). "Histamine Release from Mast Cells and Basophils". Handbook of Experimental Pharmacology. 241: 121–139. doi:10.1007/164_2017_18. ISBN 978-3-319-58192-7. PMID 28332048.
- Maintz L, Novak N (May 2007). "Histamine and histamine intolerance". The American Journal of Clinical Nutrition. 85 (5): 1185–1196. doi:10.1093/ajcn/85.5.1185. PMID 17490952.
- "Histamine Intolerance".
- Kennedy MJ, Loehle JA, Griffin AR, Doll MA, Kearns GL, Sullivan JE, Hein DW (December 2008). "Association of the histamine N-methyltransferase C314T (Thr105Ile) polymorphism with atopic dermatitis in Caucasian children". Pharmacotherapy. 28 (12): 1495–1501. doi:10.1592/phco.28.12.1495. PMC 2642612. PMID 19025430.
- Hon YY, Jusko WJ, Zhou HH, Chen GL, Guo D, Zhou G, et al. (2006). "Endogenous histamine and cortisol levels in subjects with different histamine N-methyltransferase C314T genotypes : a pilot study". Molecular Diagnosis & Therapy. 10 (2): 109–114. doi:10.1007/BF03256450. PMC 4178529. PMID 16669609.
- Fernández-Novoa L, Corzo L, Seoane S, Cacabelos R (2017). "A Genomic Approach to Histamine Function". J Genomic Med Pharmacogenomics. 1 (2): 233–241.
- Jeannin P, Delneste Y, Gosset P, Molet S, Lassalle P, Hamid Q, et al. (October 1994). "Histamine induces interleukin-8 secretion by endothelial cells". Blood. 84 (7): 2229–2233. doi:10.1182/blood.V84.7.2229.2229. PMID 7919340.
- Wang L, Thomae B, Eckloff B, Wieben E, Weinshilboum R (August 2002). "Human histamine N-methyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5'-flanking region single nucleotide polymorphism (SNP)". Biochemical Pharmacology. 64 (4): 699–710. doi:10.1016/s0006-2952(02)01223-6. PMID 12167489.
- García-Martín E, Martínez C, Benito-León J, Calleja P, Díaz-Sánchez M, Pisa D, et al. (February 2010). "Histamine-N-methyl transferase polymorphism and risk for multiple sclerosis". European Journal of Neurology. 17 (2): 335–338. doi:10.1111/j.1468-1331.2009.02720.x. PMID 19538200. S2CID 27960274.
- Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, et al. (December 2009). "Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy". Nature Genetics. 41 (12): 1345–1349. doi:10.1038/ng.478. PMID 19898482. S2CID 21293339.
- Seip RL, Volek JS, Windemuth A, Kocherla M, Fernandez ML, Kraemer WJ, Ruaño G (February 2008). "Physiogenomic comparison of human fat loss in response to diets restrictive of carbohydrate or fat". Nutrition & Metabolism. 5: 4. doi:10.1186/1743-7075-5-4. PMC 2270845. PMID 18254975.
- Chen GL, Zhu B, Nie WP, Xu ZH, Tan ZR, Zhou G, et al. (September 2004). "Single nucleotide polymorphisms and haplotypes of histamine N-methyltransferase in patients with gastric ulcer". Inflammation Research. 53 (9): 484–488. doi:10.1007/s00011-004-1290-0. PMID 15551002. S2CID 20583550.
- Szczepankiewicz A, Bręborowicz A, Sobkowiak P, Popiel A (November 2010). "Polymorphisms of two histamine-metabolizing enzymes genes and childhood allergic asthma: a case control study". Clinical and Molecular Allergy. 8: 14. doi:10.1186/1476-7961-8-14. PMC 2990726. PMID 21040557.
- Stevenson J, Sonuga-Barke E, McCann D, Grimshaw K, Parker KM, Rose-Zerilli MJ, et al. (September 2010). "The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms". The American Journal of Psychiatry. 167 (9): 1108–1115. doi:10.1176/appi.ajp.2010.09101529. PMID 20551163.
- Aksoy S, Raftogianis R, Weinshilboum R (February 1996). "Human histamine N-methyltransferase gene: structural characterization and chromosomal location". Biochemical and Biophysical Research Communications. 219 (2): 548–554. doi:10.1006/bbrc.1996.0271. PMID 8605025.
- Horton JR, Sawada K, Nishibori M, Zhang X, Cheng X (September 2001). "Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons". Structure. 9 (9): 837–849. doi:10.1016/S0969-2126(01)00643-8. PMC 4030376. PMID 11566133.
- Histamine+N-Methyltransferase at the US National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for human histamine N-methyltransferase