Histamine N-methyltransferase

{{Short description|Class of enzymes}} {{Italic title|string=N}} {{good article}} {{Use dmy dates|date=December 2023}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{enzyme | name = Histamine ''N''-methyltransferase | EC_number = 2.1.1.8 | CAS_number = 9029-80-5 | GO_code = 0046539 }} {{Infobox_gene}} '''Histamine ''N''-methyltransferase''' ('''HNMT''') is a protein encoded by the ''HNMT'' gene in humans. It belongs to the methyltransferases superfamily of enzymes and plays a role in the inactivation of histamine, a biomolecule that is involved in various physiological processes. Methyltransferases are present in every life form including archaeans, with 230 families of methyltransferases found across species.

Specifically, HNMT transfers a methyl (-CH3) group from ''S''-adenosyl-L-methionine (SAM-e) to histamine, forming an inactive metabolite called ''Nτ''-methylhistamine, in a chemical reaction called ''Nτ''-methylation. In mammals, HNMT operates alongside diamine oxidase (DAO) as the only two enzymes responsible for histamine metabolism; however, what sets HNMT apart is its unique presence within the central nervous system (CNS), where it governs histaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between the neurons—nerve cells—in the brain. By degrading and regulating levels of histamine specifically within the CNS, HNMT ensures the proper functioning of neural pathways related to arousal, appetite regulation, sleep-wake cycles, and other essential brain functions.

Research on knockout mice—that are genetically modified mice lacking the ''Hnmt'' gene—has revealed that the absence of this enzyme leads to increased brain histamine concentrations and behavioral changes such as heightened aggression and disrupted sleep patterns. These findings highlight the critical role played by HNMT in maintaining normal brain function through precise regulation of neuronal signaling involving histamine. Genetic variants affecting HNMT activity have also been implicated in various neurological disorders like Parkinson's disease and attention deficit disorder.

==Gene== {{See also|Introduction to genetics|Gene expression}} Histamine ''N''-methyltransferase is encoded by a single gene, called ''HNMT'', which has been mapped to chromosome 2 in humans.<ref name="entrez-HNMT">{{NCBI RefSeq | title = HNMT Histamine ''N''-methyltransferase | url = https://www.ncbi.nlm.nih.gov/gene/3176 | publisher = National Center for Biotechnology Information | access-date = 30 November 2020 | quote = In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene.}}{{PD-notice}}</ref>

Three transcript variants have been identified for this gene in humans, which produce different protein isoforms<ref name="uniprotkb-isoforms">{{cite web | url=https://www.uniprot.org/uniprotkb/P50135/entry#sequences | title=UniProt HNMT isoforms | access-date=27 November 2023 | archive-date=29 November 2023 | archive-url=https://web.archive.org/web/20231129013516/https://www.uniprot.org/uniprotkb/P50135/entry#sequences | url-status=live }}</ref><ref name="entrez-HNMT" /> due to alternative splicing, which allows a single gene to code for multiple proteins by including or excluding particular exons of a gene in the final mRNA produced from that gene.<ref name="pmid36229538">{{cite journal | vauthors = Marasco LE, Kornblihtt AR | title = The physiology of alternative splicing | journal = Nature Reviews. Molecular Cell Biology | volume = 24 | issue = 4 | pages = 242–254 | date = April 2023 | pmid = 36229538 | doi = 10.1038/s41580-022-00545-z | s2cid = 252896843 | hdl = 11336/213972 | hdl-access = free }}</ref><ref name="pmid36526860">{{cite journal | vauthors = Rogalska ME, Vivori C, Valcárcel J | title = Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects | journal = Nature Reviews. Genetics | volume = 24 | issue = 4 | pages = 251–269 | date = April 2023 | pmid = 36526860 | doi = 10.1038/s41576-022-00556-8 | s2cid = 254809593 }}</ref> Of those isoforms, only one has histamine-methylating activity.<ref name="uniprotkb-isoforms" />

In the human genome, six exons from the 50-kb ''HNMT'' contribute to forming a unique mRNA species, approximately 1.6 kb in size. This mRNA is then translated into the cytosolic enzyme histamine ''N''-methyltransferase, comprising 292 amino acids, of which 130 amino acids are a conserved sequence.<ref name="pmid14667820">{{cite journal | vauthors = Barnes WG, Grinde E, Crawford DR, Herrick-Davis K, Hough LB | title = Characterization of a new mRNA species from the human histamine N-methyltransferase gene | journal = Genomics | volume = 83 | issue = 1 | pages = 168–171 | date = January 2004 | pmid = 14667820 | doi = 10.1016/s0888-7543(03)00236-2 }}</ref><ref name="IPR016673-HNMT-Like">{{cite web |title=InterPro |url=https://www.ebi.ac.uk/interpro/entry/InterPro/IPR016673/ |access-date=28 November 2023 |website=www.ebi.ac.uk |archive-date=29 November 2023 |archive-url=https://web.archive.org/web/20231129013514/https://www.ebi.ac.uk/interpro/entry/InterPro/IPR016673/ |url-status=live }}</ref> ''HNMT'' does not have promoter cis-elements, such as TATA and CAAT boxes.<ref name="pmid12167489">{{cite journal | vauthors = Wang L, Thomae B, Eckloff B, Wieben E, Weinshilboum R | title = Human histamine N-methyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5'-flanking region single nucleotide polymorphism (SNP) | journal = Biochemical Pharmacology | volume = 64 | issue = 4 | pages = 699–710 | date = August 2002 | pmid = 12167489 | doi = 10.1016/S0006-2952(02)01223-6 }}</ref><ref name="pmid21814788">{{cite journal | vauthors = Reyes-Palomares A, Montañez R, Sánchez-Jiménez F, Medina MA | title = A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability | journal = Amino Acids | volume = 42 | issue = 2–3 | pages = 597–610 | date = February 2012 | pmid = 21814788 | doi = 10.1007/s00726-011-1035-7 }}</ref>

==Protein== {{See also|Protein folding}} HNMT is a cytoplasmic protein,<ref name="pmid26206890">{{cite journal | vauthors = Heidari A, Tongsook C, Najafipour R, Musante L, Vasli N, Garshasbi M, Hu H, Mittal K, McNaughton AJ, Sritharan K, Hudson M, Stehr H, Talebi S, Moradi M, Darvish H, Arshad Rafiq M, Mozhdehipanah H, Rashidinejad A, Samiei S, Ghadami M, Windpassinger C, Gillessen-Kaesbach G, Tzschach A, Ahmed I, Mikhailov A, Stavropoulos DJ, Carter MT, Keshavarz S, Ayub M, Najmabadi H, Liu X, Ropers HH, Macheroux P, Vincent JB | title = Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability | journal = Human Molecular Genetics | volume = 24 | issue = 20 | pages = 5697–5710 | date = October 2015 | pmid = 26206890 | pmc = 4581600 | doi = 10.1093/hmg/ddv286 }}</ref> meaning that it operates within the cytoplasm of a cell.<ref name="Rehfeld-2017">{{cite book|doi=10.1007/978-3-319-41873-5_3|chapter=The Cytoplasm |title=Compendium of Histology |date=2017 |pages=27–47 |isbn=978-3-319-41871-1 | vauthors = Rehfeld A, Nylander M, Karnov K }}</ref> The cytoplasm fills the space between the outer cell membrane (also known as the cellular plasma membrane) and the nuclear membrane (which surrounds the cell's nucleus).<ref name="Rehfeld-2017"/> HNMT helps regulate histamine levels by degrading histamine within the cytoplasm, ensuring proper cellular function.<ref name="Verburg-1986">{{cite book|doi=10.1385/0-89603-079-2:147|title=Histamine N-Methyltransferase|vauthors=Verburg KM, Henry DP|year=1986|volume=5|publisher=Humana Press|isbn=978-1-59259-610-2}}</ref>

Proteins consist of amino acid residues and form a three-dimensional structure. The crystallographic structure to depict the three-dimensional structure of human HNMT protein was first described in 2001 as a monomeric protein that has a mass of 33 kilodaltons and consists of two structural domains.<ref name="pmid11566133">{{cite journal | vauthors = Horton JR, Sawada K, Nishibori M, Zhang X, Cheng X | title = Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons | journal = Structure | volume = 9 | issue = 9 | pages = 837–849 | date = September 2001 | pmid = 11566133 | pmc = 4030376 | doi = 10.1016/s0969-2126(01)00643-8 }}</ref><ref name="pmid34893161"/>

The first domain, called the "MTase domain", contains the active site where methylation occurs. It has a classic fold found in many other methyltransferases and consists of a seven-stranded beta-sheet surrounded by three helices on each side. This domain binds to its cofactor, ''S''-adenosyl-L-methionine (SAM-e), which provides the methyl group for ''Nτ''-methylation reactions.<ref name="pmid11566133"/><ref name="pmid34893161"/>

The second domain, called the "substrate binding domain", interacts with histamine, contributing to its binding to the enzyme molecule. This domain is connected to the MTase domain and forms a separate region. It includes an anti-parallel beta sheet along with additional alpha helices and 310 helices.<ref name="pmid11566133"/><ref name="pmid34893161"/>

==Species== Histamine ''N''-methyltransferase belongs to methyltransferases, a superfamily of enzymes present in every life form,<ref name="IPR016673-HNMT-Like"/> including archaeans.<ref name="pmid36891755">{{cite journal | vauthors = Lee YH, Ren D, Jeon B, Liu HW | title = ''S''-Adenosylmethionine: more than just a methyl donor | journal = Natural Product Reports | volume = 40 | issue = 9 | pages = 1521–1549 | date = September 2023 | pmid = 36891755 | pmc = 10491745 | doi = 10.1039/d2np00086e }}</ref>

These enzymes catalyze methylation, which is a chemical process that involves the addition of a methyl group to a molecule, which can affect its biological function.<ref name="IPR016673-HNMT-Like"/><ref name="pmid34893161"/>

To facilitate methylation, methyltransferases transfer a methyl group (-CH3) from a cosubstrate (donor) to a substrate molecule (acceptor), leading to the formation of a methylated molecule.<ref name="IPR016673-HNMT-Like"/><ref name="pmid34893161"/> Most methyltransferases use ''S''-adenosyl-L-methionine (SAM-e) as a donor, converting it into ''S''-adenosyl-L-homocysteine (SAH).<ref name="IPR016673-HNMT-Like"/><ref name="pmid34893161"/> In various species, members of the methyltransferase superfamily of enzymes methylate a wide range of molecules, including small molecules, proteins, nucleic acids, and lipids. These enzymes are involved in numerous cellular processes such as signaling, protein repair, chromatin regulation, and gene regulation. More than 230 families of methyltransferases have been described in various species.<ref name="IPR016673-HNMT-Like"/><ref name="pmid12826405">{{cite journal | vauthors = Schubert HL, Blumenthal RM, Cheng X | title = Many paths to methyltransfer: a chronicle of convergence | journal = Trends in Biochemical Sciences | volume = 28 | issue = 6 | pages = 329–335 | date = June 2003 | pmid = 12826405 | pmc = 2758044 | doi = 10.1016/S0968-0004(03)00090-2 }}</ref>

This specific protein, histamine ''N''-methyltransferase, is found in vertebrates, including mammals, birds, reptiles, amphibians, and fishes, but not in invertebrates and plants.<ref name="pmid14667820"/><ref name="genecards-HNMT-Gene">{{cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=HNMT|title=HNMT Gene – GeneCards | HNMT Protein | HNMT Antibody|access-date=27 November 2023|archive-date=5 December 2023|archive-url=https://web.archive.org/web/20231205090600/https://www.genecards.org/cgi-bin/carddisp.pl?gene=HNMT|url-status=live}}</ref><ref name="Goulty-2023">{{cite journal | vauthors = Goulty M, Botton-Amiot G, Rosato E, Sprecher SG, Feuda R | title = The monoaminergic system is a bilaterian innovation | journal = Nature Communications | volume = 14 | issue = 1 | article-number = 3284 | date = June 2023 | pmid = 37280201 | doi = 10.1038/s41467-023-39030-2 | doi-access = free | pmc = 10244343 | bibcode = 2023NatCo..14.3284G }}</ref>

The complementary DNA (cDNA) of ''Hnmt'' was initially cloned from a rat kidney and has since been cloned from human, mouse, and guinea pig sources.<ref name="pmid14667820"/> Human HNMT shares 55.37% similarity with that of zebrafish, 86.76% with that of mouse, 90.53% with that of dog, and 99.54% with that of chimpanzee.<ref name="genecards-HNMT-Gene"/><ref name="gene445242">{{NCBI RefSeq| url=https://www.ncbi.nlm.nih.gov/gene/445242 | title=HNMT histamine N-methyltransferase [Danio rerio (Zebrafish)] – Gene – NCBI }}</ref> Moreover, expressed sequence tags from cow, pig, and gorilla, as well as genome survey sequences from pufferfish, also exhibit strong similarity to human HNMT, suggesting that it is a highly conserved protein among vertebrates.<ref name="pmid11566133"/> To understand the role of histamine ''N''-methyltransferase in brain function, researchers have studied ''Hnmt''-deficient (knockout) mice, that were genetically modified to have the ''Hnmt'' gene "knocked out", i.e., deactivated.<ref name="pmid29162912">{{cite journal | vauthors = Naganuma F, Nakamura T, Yoshikawa T, Iida T, Miura Y, Kárpáti A, Matsuzawa T, Yanai A, Mogi A, Mochizuki T, Okamura N, Yanai K | title = Histamine N-methyltransferase regulates aggression and the sleep-wake cycle | journal = Scientific Reports | volume = 7 | issue = 1 | article-number = 15899 | date = November 2017 | pmid = 29162912 | pmc = 5698467 | doi = 10.1038/s41598-017-16019-8 | bibcode = 2017NatSR...715899N }}</ref><ref name="pmid16648665">{{cite journal | vauthors = Ogasawara M, Yamauchi K, Satoh Y, Yamaji R, Inui K, Jonker JW, Schinkel AH, Maeyama K | title = Recent advances in molecular pharmacology of the histamine systems: organic cation transporters as a histamine transporter and histamine metabolism | journal = Journal of Pharmacological Sciences | volume = 101 | issue = 1 | pages = 24–30 | date = May 2006 | pmid = 16648665 | doi = 10.1254/jphs.fmj06001x6 | doi-access = free }}</ref> Scientists discovered that disrupting the gene led to a significant rise in histamine levels in the mouse brain that highlighted the role of the gene in the brain's histamine system and suggested that ''HNMT'' genetic variations in humans could be linked to brain disorders.

== Tissue and subcellular distribution ==  On subcellular distribution, histamine ''N''-methyltransferase protein in humans is mainly localized to the nucleoplasm (which is an organelle, i.e., a subunit of a cell) and cytosol (which is the intracellular fluid, i.e., a fluid inside cells). In addition, it is localized to the centrosome (another organelle).<ref name="Subcellular-2023">{{cite web | url=https://www.proteinatlas.org/ENSG00000150540-HNMT/subcellular | title=Subcellular – HNMT – the Human Protein Atlas | access-date=27 November 2023 | archive-date=29 November 2023 | archive-url=https://web.archive.org/web/20231129013516/https://www.proteinatlas.org/ENSG00000150540-HNMT/subcellular | url-status=live }}</ref>

In humans, the protein is present in many tissues and is most abundantly expressed in the brain, thyroid gland, bronchus, duodenum, liver, gallbladder, kidney, and skin.<ref name="Protein Atlas - Tissue expression of HNMT">{{cite web | url=https://www.proteinatlas.org/ENSG00000150540-HNMT/tissue | title=Tissue expression of HNMT – Summary – the Human Protein Atlas | access-date=27 November 2023 | archive-date=17 October 2023 | archive-url=https://web.archive.org/web/20231017164355/https://www.proteinatlas.org/ENSG00000150540-HNMT/tissue | url-status=live }}</ref>

== Function == [[File:HNMT-methylation-of-histamine.svg|thumb|right|class=skin-invert-image|alt=Histamine inactivation by HNMT|Biological inactivation of histamine via ''Nτ''-methylation by the histamine ''N''-methyltransferase (HNMT) enzyme using ''S''-adenosyl-L-methionine (SAM-e) as a cosubstrate and a donor of methyl (CH3) functional group (the biochemical transformation is depicted as in KEGG reaction R02155).<ref name="kegg-R02155">{{cite encyclopedia | title = Reaction for Histamine N-methyltransferase [EC:2.1.1.8] | id = R02155 | url = https://www.genome.jp/entry/R02155 | encyclopedia = KEGG: Kyoto Encyclopedia of Genes and Genomes | access-date = 29 November 2023 | archive-date = 29 November 2023 | archive-url = https://web.archive.org/web/20231129220438/https://www.genome.jp/entry/R02155 | url-status = live }}</ref> The methyl group from the cosubstrate (denoted by red oval) is transferred to histamine to ''Nτ'' position that forms ''Nτ''-methylhistamine (NMT), which has the methyl group attached (denoted by green oval). The conversion of histamine to NMT is shown by the straight arrow. The SAM-e is thereby transformed to ''S''-adenosyl-L-histidine (SAH), a molecule without the methyl group. The conversion of SAM-e to SAH is shown by the curved arrow.<ref name="pmid33310825"/><ref name="pmid34893161"/>]]The function of the HNMT enzyme is histamine metabolism by ways of ''Nτ''-methylation using ''S''-adenosyl-L-methionine (SAM-e) as the methyl donor, producing ''Nτ''-methylhistamine, which, unless excreted, can be further processed by monoamine oxidase B (MAOB) or by diamine oxidase (DAO). Methylated histamine metabolites are excreted with urine.<ref name="pmid11566133"/><ref name="pmid34893161"/>

In mammals, there are two main ways to inactivate histamine by metabolism: one is through a process called oxidative deamination, which involves the enzyme diamine oxidase (DAO) produced by the ''AOC1'' gene, and the other is through a process called ''Nτ''-methylation, which involves the enzyme ''N''-methyltransferase.<ref name="Kucher-2018">{{cite journal | vauthors = Kucher AN, Cherevko NA |title=Genes of the Histamine Pathway and Common Diseases |journal=Russian Journal of Genetics |date=2018 |volume=54 |issue=1 |pages=15–32 |doi=10.1134/S1022795418010088 }}</ref> In the context of biochemistry, inactivation by metabolism refers to the process where a substance, such as a hormone, is converted into a form that is no longer active or effective (''inactivation''), via a process where the substance is chemically altered (''metabolism'').<ref name="Midtvedt-1987">{{cite book|doi=10.1007/978-94-009-3353-8_7|isbn=978-94-009-3353-8|year=1987 |chapter=Metabolism of Endogenous Substances |title=Frontiers in Microbiology |pages=79–88 | vauthors = Midtvedt T }}</ref><ref name="Drug-Metabolism-Pathways-Biotr-2005">{{cite book|doi=10.1007/1-4020-4142-X_2|isbn=978-1-4020-4142-6|year=2005 |chapter=Pathways of Biotransformation — Phase I Reactions |title=Drug Metabolism |pages=41–128 }}</ref><ref name="Caira-2006">{{cite book|isbn=978-1-4020-4142-6 |title=Drug Metabolism: Current Concepts |date=10 July 2006 |publisher=Springer | vauthors = Caira MR, Ionescu C }}</ref><ref name="Drug-Metabolism-ClinPh">{{cite web|url=https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism|title=Drug Metabolism – Clinical Pharmacology|access-date=17 April 2024|archive-date=27 November 2022|archive-url=https://web.archive.org/web/20221127042834/https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism|url-status=live}}</ref>

HNMT and DAO are two enzymes that play distinct roles in histamine metabolism. DAO is primarily responsible for metabolizing histamine in extracellular (outside cells) fluids,<ref name="pmid22686593">{{cite journal | vauthors = Dou Y, Zhu F, Kotanko P | title = Assessment of extracellular fluid volume and fluid status in hemodialysis patients: current status and technical advances | journal = Seminars in Dialysis | volume = 25 | issue = 4 | pages = 377–387 | date = July 2012 | pmid = 22686593 | doi = 10.1111/j.1525-139X.2012.01095.x | quote = Extracellular fluid is distributed in two major sub-compartments: interstitial fluid and plasma }}</ref><ref name="pmid36931880"/><ref name="pmid18499706"/> which include interstitial fluid<ref name="pmid4400180">{{cite journal | vauthors = Cox JS | title = Disodium cromoglycate. Mode of action and its possible relevance to the clinical use of the drug | journal = British Journal of Diseases of the Chest | volume = 65 | issue = 4 | pages = 189–204 | date = October 1971 | pmid = 4400180 | doi = 10.1016/0007-0971(71)90028-3 }}</ref><ref name="pmid414862">{{cite journal | vauthors = Yamamoto S, Francis D, Greaves MW | title = Enzymic histamine catabolism in skin and its possible clinical significance: a review | journal = Clinical and Experimental Dermatology | volume = 2 | issue = 4 | pages = 389–393 | date = December 1977 | pmid = 414862 | doi = 10.1111/j.1365-2230.1977.tb01580.x }}</ref> (fluid surrounding cells) and blood plasma.<ref name="pmid30418682">{{cite journal | vauthors = Boehm T, Reiter B, Ristl R, Petroczi K, Sperr W, Stimpfl T, Valent P, Jilma B | title = Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients | journal = Allergy | volume = 74 | issue = 3 | pages = 583–593 | date = March 2019 | pmid = 30418682 | pmc = 6590243 | doi = 10.1111/all.13663 }}</ref> Such histamine can be exogenous (from food or intestinal flora) or endogenous (released from granules of mast cells and basophils, such as during allergic reactions).<ref name="pmid36931880">{{cite journal | vauthors = Hakl R, Litzman J | title = Histamine intolerance | journal = Vnitrni Lekarstvi | volume = 69 | issue = 1 | pages = 37–40 | date = 2023 | pmid = 36931880 | doi = 10.36290/vnl.2023.005 | s2cid = 257604532 | doi-access = free }}</ref> DAO is predominantly expressed in the cells of the intestinal epithelium and placenta but not in the central nervous system (CNS).<ref name="pmid18499706">{{cite journal | vauthors = Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N | title = Effects of histamine and diamine oxidase activities on pregnancy: a critical review | journal = Human Reproduction Update | volume = 14 | issue = 5 | pages = 485–495 | date = 2008 | pmid = 18499706 | doi = 10.1093/humupd/dmn014 | doi-access = free }}</ref><ref name="pmid17490952"/> In contrast, HNMT is expressed in CNS and involved in the metabolism of intracellular (inside cells) histamine, which is primarily endogenous and persistently present. HNMT operates in the cytosol, which is the fluid inside cells. Histamine is required to be carried into the cytosol through transporters<ref name="pmid27679412">{{cite book | vauthors = Yoshikawa T, Yanai K | title = Histamine and Histamine Receptors in Health and Disease | chapter = Histamine Clearance Through Polyspecific Transporters in the Brain | volume = 241 | pages = 173–187 | date = 28 September 2016 | pmid = 27679412 | doi = 10.1007/164_2016_13 | isbn = 978-3-319-58192-7 | series = Handbook of Experimental Pharmacology }}</ref> such as plasma membrane monoamine transporter (SLC29A4) or organic cation transporter 3 (SLC22A3). HNMT enzyme is found in cells of diverse tissues: neurons and glia, brain, kidneys, liver, bronchi, large intestine, ovary, prostate, spinal cord, spleen, and trachea, etc.<ref name="pmid33310825">{{cite journal | vauthors = Verhoeven WM, Egger JI, Janssen PK, van Haeringen A | title = Adult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene | journal = BMJ Case Reports | volume = 13 | issue = 12 | article-number = e235972 | date = December 2020 | pmid = 33310825 | pmc = 7735107 | doi = 10.1136/bcr-2020-235972 }}</ref><ref name="pmid28332048">{{cite book | vauthors = Borriello F, Iannone R, Marone G | title = Histamine and Histamine Receptors in Health and Disease | chapter = Histamine Release from Mast Cells and Basophils | series = Handbook of Experimental Pharmacology | volume = 241 | pages = 121–139 | year = 2017 | publisher = Springer | pmid = 28332048 | doi = 10.1007/164_2017_18 | isbn = 978-3-319-58192-7 }}</ref><ref name="pmid17490952"/> While DAO is primarily found in the intestinal epithelium, HNMT is present in a wider range of tissues throughout the body. This difference in location also requires different transport mechanisms for histamine to reach each enzyme, reflecting the distinct roles of these enzymes in histamine metabolism. Another distinction between HNMT and DAO lies in their substrate specificity. While HNMT has a strong preference for histamine, DAO can metabolize other biogenic amines—substances, produced by a life form (like a bacteria or an animal) that has an amine functional group (−NH2).<ref name="Verburg-1986"/><ref name="pmid28791419">{{cite journal | vauthors = Schwelberger HG, Feurle J, Houen G | title = Mapping of the binding sites of human histamine N-methyltransferase (HNMT) monoclonal antibodies | journal = Inflammation Research | volume = 66 | issue = 11 | pages = 1021–1029 | date = November 2017 | pmid = 28791419 | pmc = 5633628 | doi = 10.1007/s00011-017-1086-7 }}</ref> The examples of biogenic amines besides histamine that DAO can metabolize are putrescine and cadaverine;<ref name="pmid36208352">{{cite journal | vauthors = Kettner L, Seitl I, Fischer L | title = Recent advances in the application of microbial diamine oxidases and other histamine-oxidizing enzymes | journal = World Journal of Microbiology & Biotechnology | volume = 38 | issue = 12 | article-number = 232 | date = October 2022 | pmid = 36208352 | pmc = 9547800 | doi = 10.1007/s11274-022-03421-2 }}</ref> still, DAO has a preference for histamine.<ref name="pmid29181545">{{cite journal | vauthors = Schnedl WJ, Lackner S, Enko D, Schenk M, Mangge H, Holasek SJ | title = Non-celiac gluten sensitivity: people without celiac disease avoiding gluten-is it due to histamine intolerance? | journal = Inflammation Research | volume = 67 | issue = 4 | pages = 279–284 | date = April 2018 | pmid = 29181545 | doi = 10.1007/s00011-017-1117-4 }}</ref> Both DAO and HNMT exhibit comparable affinities toward histamine.<ref name="pmid17490952"/><ref name="Schwelberger-2013">{{cite book | vauthors=Schwelberger HG, Ahrens F, Fogel WS, Sánchez-Jiménez F | chapter=Chapter 3 Histamine Metabolism | chapter-url=https://www.degruyter.com/document/doi/10.2478/9788376560564.c3/pdf?licenseType=free | veditors = Stark H | title=Histamine H4 Receptor: A Novel Drug Target in Immunoregulation and Inflammation | doi=10.2478/9788376560564.c3 | date=2013 | pages=63–102 | isbn=978-83-7656-054-0 | access-date=20 April 2024 | archive-date=20 April 2024 | archive-url=https://web.archive.org/web/20240420081054/https://www.degruyter.com/document/doi/10.2478/9788376560564.c3/pdf?licenseType=free | url-status=live }}</ref>

In the brain of mammals, histamine takes part in histaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between the neurons—the nerve cells.<ref name="pmid37123051"/> Histamine neurotransmitter activity is controlled by HNMT, since DAO is not present in the CNS.<ref name="entrez-HNMT"/> Consequently, the deactivation of histamine via HNMT represents the sole mechanism for ending neurotransmission within the mammalian CNS.<ref name="pmid33310825"/> This highlights the key role of HNMT for the histamine system of the brain and the brain function in general.<ref name="pmid33310825"/>

==Physiological and clinical significance== ===Role in health=== {{See also|Histamine}} Histamine has important roles in human physiology as both a hormone and a neurotransmitter. As a hormone, it is involved in the inflammatory response and itching. It regulates physiological functions in the gut and acts on the brain, spinal cord, and uterus.<ref name="pmid21277530"/><ref name="pmid34448132"/> As a neurotransmitter, histamine promotes arousal and regulates appetite and the sleep-wake cycle.<ref name="pmid34432259">{{cite book|doi=10.1007/7854_2021_235 |chapter=Histamine in the Crosstalk Between Innate Immune Cells and Neurons: Relevance for Brain Homeostasis and Disease |title=The Functional Roles of Histamine Receptors |series=Current Topics in Behavioral Neurosciences |date=2021 |volume=59 |pages=261–288 |pmid=34432259 |isbn=978-3-031-16996-0 | vauthors = Bernardino L }}</ref><ref name="pmid18626069">{{cite journal | vauthors = Haas HL, Sergeeva OA, Selbach O | title = Histamine in the nervous system | journal = Physiological Reviews | volume = 88 | issue = 3 | pages = 1183–1241 | date = July 2008 | pmid = 18626069 | doi = 10.1152/physrev.00043.2007 }}</ref><ref name="pmid37123051">{{cite journal | vauthors = Satpati A, Neylan T, Grinberg LT | title = Histaminergic neurotransmission in aging and Alzheimer's disease: A review of therapeutic opportunities and gaps | journal = Alzheimer's & Dementia | volume = 9 | issue = 2 | article-number = e12379 | date = 2023 | pmid = 37123051 | pmc = 10130560 | doi = 10.1002/trc2.12379 }}</ref> It also affects vasodilation, fluid production in tissues like the nose and eyes, gastric acid secretion, sexual function, and immune responses.<ref name="pmid21277530">{{cite journal | vauthors = Lieberman P | title = The basics of histamine biology | journal = Annals of Allergy, Asthma & Immunology | volume = 106 | issue = 2 Suppl | pages = S2–S5 | date = February 2011 | pmid = 21277530 | doi = 10.1016/j.anai.2010.08.005 }}</ref><ref name="pmid34448132">{{cite book | vauthors = Mochizuki T | title = The Functional Roles of Histamine Receptors | chapter = Histamine as an Alert Signal in the Brain | volume = 59 | pages = 413–425 | date = 2022 | pmid = 34448132 | doi = 10.1007/7854_2021_249 | isbn = 978-3-031-16996-0 | series = Current Topics in Behavioral Neurosciences | s2cid = 237329317 }}</ref>

HNMT is the only enzyme in the human body responsible for metabolizing histamine within the CNS, playing a role in brain function.<ref name="pmid29162912"/><ref name="pmid27679412"/>

HNMT plays a role in maintaining the proper balance of histamine in the human body. HNMT is responsible for the breakdown and metabolism of histamine, converting it into an inactive metabolite, ''Nτ''-methylhistamine,<ref name="pmid21277530"/><ref name="pmid34448132"/> which inhibits ''HNMT'' gene expression in a negative feedback loop.<ref name="pmid25164630">{{cite journal | vauthors = Peters LJ, Kovacic JP | title = Histamine: metabolism, physiology, and pathophysiology with applications in veterinary medicine | journal = Journal of Veterinary Emergency and Critical Care | volume = 19 | issue = 4 | pages = 311–328 | date = August 2009 | pmid = 25164630 | doi = 10.1111/j.1476-4431.2009.00434.x }}</ref> By metabolizing histamine, HNMT helps prevent excessive levels of histamine from accumulating in various tissues and organs. This enzymatic activity ensures that histamine remains at appropriate levels to carry out its physiological functions without causing unwanted effects or triggering allergic reactions. In the central nervous system, HNMT plays an essential role in degrading histamine, where it acts as a neurotransmitter, since HNMT is the only enzyme in the body that can metabolize histamine in the CNS, ending its neurotransmitter activity.<ref name="pmid21277530"/><ref name="pmid34448132"/>

HNMT also plays a role in the airway response to harmful particles,<ref name="uniprotkb-main">{{cite web | url=https://www.uniprot.org/uniprotkb/P50135/entry | title=UniProt HNMT | access-date=27 November 2023 | archive-date=29 November 2023 | archive-url=https://web.archive.org/web/20231129013516/https://www.uniprot.org/uniprotkb/P50135/entry | url-status=live }}</ref> which is the body's physiological reaction to immune allergens, bacteria, or viruses in the respiratory system. Histamine is stored in granules in mast cells, basophils, and in the synaptic vesicles of histaminergic neurons of the airways. When exposed to immune allergens or harmful particles, histamine is released from these storage granules and quickly diffuses into the surrounding tissues. However, the released histamine needs to be rapidly deactivated for proper regulation, which is a function of HNMT.<ref name="pmid1846044">{{cite journal | vauthors = Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M | title = Histaminergic transmission in the mammalian brain | journal = Physiological Reviews | volume = 71 | issue = 1 | pages = 1–51 | date = January 1991 | pmid = 1846044 | doi = 10.1152/physrev.1991.71.1.1 }}</ref><ref name="pmid31101811">{{cite journal | vauthors = Sande CJ, Njunge JM, Mwongeli Ngoi J, Mutunga MN, Chege T, Gicheru ET, Gardiner EM, Gwela A, Green CA, Drysdale SB, Berkley JA, Nokes DJ, Pollard AJ | title = Airway response to respiratory syncytial virus has incidental antibacterial effects | journal = Nature Communications | volume = 10 | issue = 1 | article-number = 2218 | date = May 2019 | pmid = 31101811 | pmc = 6525170 | doi = 10.1038/s41467-019-10222-z | bibcode = 2019NatCo..10.2218S }}</ref>

===Histamine intolerance=== {{Main article |Histamine intolerance}} Histamine intolerance is a presumed set of adverse reactions to ingested histamine in food believed to be associated with flawed activity of DAO and HNMT enzymes.<ref name="pmid34651098"/> This set of reactions include cutaneous reactions (such as itching, flushing and edema), gastrointestinal symptoms (such as abdominal pain and diarrhea), respiratory symptoms (such as runny nose and nasal congestion), and neurological symptoms (such as dizziness and headache).<ref name="pmid34651098"/><ref name="pmid27679412"/> However, belief in a link between DAO and HNMT enzymes and adverse reactions to ingested histamine in food is not shared by mainstream science due to insufficient evidence.<ref name="pmid34651098">{{cite journal | vauthors = Reese I, Ballmer-Weber B, Beyer K, Dölle-Bierke S, Kleine-Tebbe J, Klimek L, Lämmel S, Lepp U, Saloga J, Schäfer C, Szepfalusi Z, Treudler R, Werfel T, Zuberbier T, Worm M | title = Guideline on management of suspected adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergology and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA) as well as the Swiss Society for Allergology and Immunology (SGAI) and the Austrian Society for Allergology and Immunology (ÖGAI) | journal = Allergologie Select | volume = 5 | issue = | pages = 305–314 | date = 2021 | pmid = 34651098 | pmc = 8511827 | doi = 10.5414/ALX02269E }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref> The exact underlying mechanisms by which deficiency in these enzymes can cause these adverse reactions are not fully understood but are hypothesized to involve genetic factors.<ref name="pmid34651098"/> Despite extensive research, there are no definitive, objective measures or indicators that could unambiguously define histamine intolerance as a distinct medical condition.<ref name="pmid34651098"/>

===Activity measurements=== The activity of HNMT, unlike that of DAO, cannot be measured by blood (serum) analysis.<ref name="pmid26206890" /><ref name="pmid1907425">{{cite journal | vauthors = Scott MC, Guerciolini R, Szumlanski C, Weinshilboum RM | title = Mouse kidney histamine N-methyltransferase: assay conditions, biochemical properties and strain variation | journal = Agents and Actions | volume = 32 | issue = 3–4 | pages = 194–202 | date = March 1991 | pmid = 1907425 | doi = 10.1007/BF01980873 | s2cid = 35519684 }}</ref>

Organs that produce DAO continuously release it into the bloodstream. DAO is stored in vesicular structures associated with the plasma membrane in epithelial cells.<ref name="pmid17490952">{{cite journal | vauthors = Maintz L, Novak N | title = Histamine and histamine intolerance | journal = The American Journal of Clinical Nutrition | volume = 85 | issue = 5 | pages = 1185–1196 | date = May 2007 | pmid = 17490952 | doi = 10.1093/ajcn/85.5.1185 | doi-access = free }}</ref> As a result, serum DAO activity can be measured, but not HNMT. This is because HNMT is primarily found within the cells of internal organs like the brain or liver and is not released to the bloodstream. Measuring intracellular HNMT directly is challenging. Therefore, diagnosis of HNMT activity is typically done indirectly by testing for known genetic variants.<ref name="pmid17490952"/>

=== Genetic variants === There is a genetic variant, registered in the Single Nucleotide Polymorphism database (dbSNP) as rs11558538, found in 10% of the population worldwide,<ref name="rs11558538">{{NCBI RefSeq|url=https://www.ncbi.nlm.nih.gov/snp/rs11558538|title=rs11558538 RefSNP Report – dbSNP – NCBI}}</ref> which means that the T allele presents at position 314 of ''HNMT'' instead of a usual C allele (c.314C>T). This variant causes the protein to be synthesized with threonine (Thr) replaced with isoleucine (Ile) at position 105 (p.Thr105Ile, T105I). This variant is described as loss-of-function allele reducing HNMT activity, and is associated with diseases such as asthma, allergic rhinitis, and atopic eczema (atopic dermatitis). For individuals with this variant, the intake of HNMT inhibitors, which hamper enzyme activity, and histamine liberators, which release histamine from the granules of mast cells and basophils, could potentially influence their histamine levels.<ref name="pmid19450133">{{cite journal | vauthors = García-Martín E, Ayuso P, Martínez C, Blanca M, Agúndez JA | title = Histamine pharmacogenomics | journal = Pharmacogenomics | volume = 10 | issue = 5 | pages = 867–883 | date = May 2009 | pmid = 19450133 | doi = 10.2217/pgs.09.26 }}</ref> Still, this genetic variant is associated with a reduced risk of Parkinson's disease.<ref name="pmid36378841">{{cite journal | vauthors = Lu Y, Dong CZ, Bao D, Zhong C, Liu K, Chen L, Wang W, Yang B | title = The Thr105Ile Variant (rs11558538) of the Histamine N-methyltransferase Gene may be associated with Reduced Risk of Parkinson Disease: A Meta-analysis | journal = Genetic Testing and Molecular Biomarkers | volume = 26 | issue = 11 | pages = 543–549 | date = November 2022 | pmid = 36378841 | doi = 10.1089/gtmb.2021.0299 | s2cid = 253551556 }}</ref><ref name="pmid27399132">{{cite journal | vauthors = Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JA | title = Thr105Ile (rs11558538) polymorphism in the histamine N-methyltransferase (HNMT) gene and risk for Parkinson disease: A PRISMA-compliant systematic review and meta-analysis | journal = Medicine | volume = 95 | issue = 27 | article-number = e4147 | date = July 2016 | pmid = 27399132 | pmc = 5058861 | doi = 10.1097/MD.0000000000004147 }}</ref><ref name="pmid34893161">{{cite journal | vauthors = Li J, Sun C, Cai W, Li J, Rosen BP, Chen J | title = Insights into S-adenosyl-l-methionine (SAM)-dependent methyltransferase related diseases and genetic polymorphisms | journal = Mutation Research/Reviews in Mutation Research | volume = 788 | article-number = 108396 | date = 2021 | pmid = 34893161 | pmc = 8847900 | doi = 10.1016/j.mrrev.2021.108396 | bibcode = 2021MRRMR.78808396L }}</ref>

Experiments involving ''Hnmt''-knockout mice have shown that a deficiency in HNMT indeed leads to increased brain histamine concentrations, resulting in heightened aggressive behaviors and disrupted sleep-wake cycles in these mice. In humans, genetic variants that affect HNMT activity have been implicated in various brain disorders, such as Parkinson's disease and attention deficit disorder, but it remains unclear whether these alterations in HNMT are a primary cause or secondary effect of these conditions. Additionally, reduced histamine levels in cerebrospinal fluid have been consistently reported in patients with narcolepsy and other conditions characterized by excessive daytime sleepiness. The association between ''HNMT'' polymorphisms and gastrointestinal diseases is still uncertain. While mild polymorphisms can lead to diseases such as asthma and inflammatory bowel disease, they may also reduce the risk of brain disorders like Parkinson's disease. On the other hand, severe mutations in ''HNMT'' can result in intellectual disability. Despite these findings, the role of HNMT in human health is not fully understood and continues to be an active area of research.<ref name="pmid33310825"/>

===Inhibitors=== The following substances are known to be HNMT inhibitors: amodiaquine, chloroquine, dimaprit, etoprine, metoprine, quinacrine, SKF-91488, tacrine, and diphenhydramine.<ref name="pmid16168438"/><ref name="Pavadai-2012"/> HNMT inhibitors may increase histamine levels in peripheral tissues and aggravate conditions associated with histamine excess, such as allergic rhinitis, urticaria, and peptic ulcer disease. {{As of|2024|lc=n|post=,}} the effect of HNMT inhibitors on brain function is not yet fully understood. Research suggests that using new inhibitors of HNMT to increase the levels of histamine in the brain could potentially contribute to improvements in the treatment of brain disorders.<ref name="pmid16168438">{{cite journal | vauthors = Horton JR, Sawada K, Nishibori M, Cheng X | title = Structural basis for inhibition of histamine N-methyltransferase by diverse drugs | journal = Journal of Molecular Biology | volume = 353 | issue = 2 | pages = 334–344 | date = October 2005 | pmid = 16168438 | pmc = 4021489 | doi = 10.1016/j.jmb.2005.08.040 }}</ref><ref name="Pavadai-2012">{{cite journal|doi=10.1016/j.jtice.2012.01.004|title=Pharmacophore modeling, virtual screening and docking studies to identify novel HNMT inhibitors|date=2012 |vauthors=Pavadai L|journal=Journal of the Taiwan Institute of Chemical Engineers |volume=43 |issue=4 |pages=493–503 }}</ref>

===Methamphetamine overdose=== {{See also|Methamphetamine#Overdose}} HNMT could be a potential target for the treatment of symptoms of methamphetamine overdose.<ref name="pmid26966348">{{cite journal | vauthors = Kitanaka J, Kitanaka N, Hall FS, Uhl GR, Takemura M | title = Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose | journal = Drug Target Insights | volume = 10 | pages = 1–7 | year = 2016 | pmid = 26966348 | pmc = 4777238 | doi = 10.4137/DTI.S38342 }}</ref> It is a central nervous system stimulant, which can be abused up to the lethal consequences: numerous deaths related to methamphetamine overdoses have been reported.<ref name="National-Institute- on-Drug-Abuse-2021">{{cite web|url=https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates|title=Overdose Death Rates|date=29 January 2021|website=National Institute on Drug Abuse|access-date=8 October 2020|archive-date=25 January 2018|archive-url=https://web.archive.org/web/20180125182059/https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates|url-status=live}}</ref> The reasoning behind this is that such overdose often leads to behavioral abnormalities, and it has been observed that elevated levels of histamine in the brain can attenuate these methamphetamine-induced behaviors. Therefore, by targeting HNMT, it might be possible to increase the levels of histamine in the brain, which could, in turn, help to mitigate the effects of a methamphetamine overdose. This effect could be achieved by using HNMT inhibitors. Studies predict that one such inhibitor can be metoprine, which crosses the blood-brain barrier and can potentially increase brain histamine levels by inhibiting HNMT; still, {{as of|2024|lc=y|post=,}} treatment of methamphetamine overdose by HNMT inhibitors is still an area of research.<ref name="pmid26966348"/>

=== ''Nτ''-methylhistamine === {{Main article|1-Methylhistamine}} ''Nτ''-methylhistamine (NτMH), also known as 1-methylhistamine, is a product of ''Nτ''-methylation of histamine in a reaction catalyzed by the HNMT enzyme.<ref name="kegg-R02155"/><ref name="pmid11566133"/><ref name="pmid34893161"/>

NτMH is considered a biologically inactive metabolite of histamine.<ref name="pmid913915">{{cite journal | vauthors = Maslinski S, Schippert B, Kovar KA, Sewing KF | title = Methylation of histamine in the gastric mucosa | journal = Digestion | volume = 15 | issue = 6 | pages = 497–505 | date = 1977 | pmid = 913915 | doi = 10.1159/000198040 }}</ref><ref name="pmid11020472">{{cite journal | vauthors = Murray S, Taylor GW, Karim QN, Bliss P, Calam J | title = N alpha-methylhistamine: association with Helicobacter pylori infection in humans and effects on gastric acid secretion | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 301 | issue = 1–2 | pages = 181–192 | date = November 2000 | pmid = 11020472 | doi = 10.1016/s0009-8981(00)00357-0 }}</ref><ref name="pmid15476285">{{cite journal | vauthors = Grassmann S, Apelt J, Ligneau X, Pertz HH, Arrang JM, Ganellin CR, Schwartz JC, Schunack W, Stark H | title = Search for histamine H(3) receptor ligands with combined inhibitory potency at histamine N-methyltransferase: omega-piperidinoalkanamine derivatives | journal = Archiv der Pharmazie | volume = 337 | issue = 10 | pages = 533–545 | date = October 2004 | pmid = 15476285 | doi = 10.1002/ardp.200400897 | s2cid = 19755327 }}</ref> NτMH is excreted in the urine and can be measured to estimate the amounts of active histamine in the body.<ref name="Lewiecki-2013" /> While NτMH has some biological activity on its own, it is much weaker than histamine. NτMH can bind to histamine receptors but has a lower affinity and efficacy than histamine for these receptors, meaning that it binds less strongly and activates them less effectively. Depending on the receptor subtype and the tissue context, NτMH may act as a partial agonist or an antagonist for some histamine receptors. NτMH may have some modulatory effects on histamine signaling, but it is unlikely to cause significant allergic or inflammatory reactions by itself. NτMH may also serve as a feedback mechanism to regulate histamine levels and prevent excessive histamine release.<ref name="Mohammed-2010">{{cite book|doi=10.1007/978-90-481-9349-3_4|chapter=Biological and Pharmacological Aspects of Histamine Receptors and Their Ligands |title=Biomedical Aspects of Histamine |year=2010 |vauthors=Mohammed T|pages=61–100 |publisher=Springer |isbn=978-90-481-9348-6 }}</ref> Still, NMT, being a product in a reaction catalyzed by HNMT, may inhibit expression of HNMT in a negative feedback loop.<ref name="pmid25164630"/>

Urinary NτMH can be measured in clinical settings when systemic mastocytosis is suspected. Systemic mastocytosis and anaphylaxis are typically associated with at least a two-fold increase in urinary NτMH levels, which are also increased in patients taking monoamine oxidase inhibitors and in patients on histamine-rich diets.<ref name="Lewiecki-2013">{{cite book|doi=10.1016/B978-0-12-415853-5.00063-7|title=Chapter 63 - Evaluation of the Patient at Risk for Osteoporosis|chapter=Evaluation of the Patient at Risk for Osteoporosis |year=2013 |vauthors=Lewiecki M|pages=1481–1504 |publisher=Academic Press |isbn=978-0-12-415853-5 }}</ref>

== References == {{Reflist}} {{NLM content}}

== External links == * {{MeshName|Histamine+N-Methyltransferase}} * [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P50135 PDBe-KB] provides an overview of all the structure information available in the PDB for human histamine ''N''-methyltransferase

{{Neurotransmitter metabolism enzymes}} {{Histaminergics}} {{One carbon transferases}} {{Enzymes}} {{Portal bar|Biology|border=no}}  {{Authority control}}  Category:EC 2.1.1 Category:Histamine Category:Enzymes Category:Metabolism Category:Human proteins