Histamine N-methyltransferase

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.[5] Histamine N-methyltransferase is encoded by a single gene, HNMT, which in humans has been mapped to chromosome 2.[6]

HNMT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHNMT, HMT, HNMT-S1, HNMT-S2, MRT51, histamine N-methyltransferase, Histamine N-methyltransferase
External IDsOMIM: 605238 MGI: 2153181 HomoloGene: 5032 GeneCards: HNMT
Gene location (Human)
Chr.Chromosome 2 (human)[1]
Band2q22.1Start137,964,020 bp[1]
End138,016,364 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

3176

140483

Ensembl

ENSG00000150540

ENSMUSG00000026986

UniProt

P50135

Q91VF2

RefSeq (mRNA)

NM_001024074
NM_001024075
NM_006895

NM_080462

RefSeq (protein)

NP_001019245
NP_001019246
NP_008826

NP_536710

Location (UCSC)Chr 2: 137.96 – 138.02 MbChr 2: 24 – 24.05 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
histamine N-methyltransferase
Identifiers
EC number2.1.1.8
CAS number9029-80-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Function

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.[6]

As about the biologic species, the HNMT enzyme is found in vertebrates, including birds, reptiles and amphibian, but not in invertebrates and plants.[7]

The NHMT 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[8] 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[9] and peripheral tissues.[7] 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.[10] Overall, the symptoms of flawed NHMT activity are typical of symptoms of histamine intolerance, including allergic rhinitis, urticaria (hives), and peptic ulcer disease.[7]

See also: Histamine intolerance

Measurements

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,[9] 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 polymorphisms. 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.[10]

Polymorphisms

The most studied polymorphism is a genetic variant C314T (rs11558538, 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).[11] Therefore, carriers of the C314T polymorphism should avoid intake of HNMT inhibitors which hamper enzyme activity. The carriers of this polymorphism should also avoid intake of histamine liberators which release histamine from granules of mast cells and basophils.[10] 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 vs 631 U/mL of red blood cells).[12] In another study of 195 subjects, the C314T polymorphism 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 vs 2.1) and higher levels of histamine (107.0 ± 53.9 vs. 85.6 ± 45.7 ng/mL) in comparison with individuals with the CC genotype.[13] This effect may indicate that there may be a link between this polymorphism and inflammation. Although the relationship between histamine and IL-8 has not been fully studied, 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.[14]

Other polymorphisms have been also identified to affect enzyme function. The A939G (3′-UTR, rs1050891) polymorphism leads to increased enzymatic activity (messenger RNA stability), while G179A (rs758252808, Gly60Asp) and T632C (rs745756308, Leu208Pro) lead to decreased enzymatic activity.[7]

Inhibitors

The following substances are known to be NHMT 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 NHMT 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.[7]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000150540 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026986 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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): 2948–50. PMID 13804910.
  6. "Entrez Gene: Histamine N-methyltransferase".
  7. 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.
  8. 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.
  9. Maintz L, Novak N (May 2007). "Histamine and histamine intolerance". The American Journal of Clinical Nutrition. 85 (5): 1185–96. doi:10.1093/ajcn/85.5.1185. PMID 17490952.
  10. "Histamine Intolerance".
  11. 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): 1495–501. doi:10.1592/phco.28.12.1495. PMC 2642612. PMID 19025430.
  12. 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): 109–14. doi:10.1007/BF03256450. PMC 4178529. PMID 16669609.
  13. Fernández-Novoa L, Corzo L, Seoane S, Cacabelos R (2017). "A Genomic Approach to Histamine Function" (PDF). J Genomic Med Pharmacogenomics. 1 (2): 233–41.
  14. 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): 2229–33. doi:10.1182/blood.V84.7.2229.2229. PMID 7919340.

Further reading

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