| HistamineN-methyltransferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 2.1.1.8 | ||||||||
| CAS no. | 9029-80-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
HistamineN-methyltransferase (HNMT) is aprotein encoded by theHNMTgene in humans. It belongs to themethyltransferasessuperfamily ofenzymes and plays a role in the inactivation of histamine, abiomolecule that is involved in variousphysiological processes. Methyltransferases are present in every life form includingarchaeans, with 230 families of methyltransferases found acrossspecies.
Specifically, HNMT transfers a methyl (-CH3) group fromS-adenosyl-L-methionine (SAM-e) tohistamine, forming an inactivemetabolite calledNτ-methylhistamine, in a chemical reaction calledNτ-methylation. Inmammals, HNMT operates alongsidediamine oxidase (DAO) as the only two enzymes responsible for histamine metabolism; however, what sets HNMT apart is its unique presence within thecentral nervous system (CNS), where it governs histaminergicneurotransmission, that is a process where histamine acts as a messenger molecule between theneurons—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 toarousal, appetite regulation,sleep-wake cycles, and other essential brain functions.
Research onknockout mice—that are genetically modified mice lacking theHnmt 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 likeParkinson's disease andattention deficit disorder.
HistamineN-methyltransferase isencoded by a singlegene, calledHNMT, which has been mapped tochromosome 2 in humans.[5]
Three transcript variants have been identified for this gene in humans, which produce different proteinisoforms[6][5] due toalternative splicing, which allows a single gene to code for multiple proteins by including or excluding particularexons of a gene in the finalmRNA produced from that gene.[7][8] Of thoseisoforms, only one has histamine-methylating activity.[6]
In the human genome, six exons from the 50-kbHNMT contribute to forming a uniquemRNA species, approximately 1.6kb in size. This mRNA is then translated into the cytosolic enzyme histamineN-methyltransferase, comprising 292amino acids, of which 130 amino acids are aconserved sequence.[9][10]HNMT does not havepromoter cis-elements, such asTATA andCAAT boxes.[11][12]
HNMT is a cytoplasmicprotein,[13] meaning that it operates within thecytoplasm of a cell.[14] The cytoplasm fills the space between the outercell membrane (also known as the cellular plasma membrane) and thenuclear membrane (which surrounds the cell's nucleus).[14] HNMT helps regulate histamine levels by degrading histamine within the cytoplasm, ensuring proper cellular function.[15]
Proteins consist of amino acid residues and form a three-dimensional structure. Thecrystallographic structure to depict the three-dimensional structure of human HNMT protein was first described in 2001 as amonomeric protein that has a mass of 33kilodaltons and consists of twostructural domains.[16][17]
The first domain, called the "MTase domain", contains the active site wheremethylation occurs. It has a classic fold found in many othermethyltransferases and consists of a seven-stranded beta-sheet surrounded by threehelices on each side. This domain binds to itscofactor,S-adenosyl-L-methionine (SAM-e), which provides themethyl group forNτ-methylation reactions.[16][17]
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 ananti-parallel beta sheet along with additionalalpha helices and 310helices.[16][17]
HistamineN-methyltransferase belongs to methyltransferases, asuperfamily ofenzymes present in every life form,[10] includingarchaeans.[18]
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.[10][17]
To facilitate methylation, methyltransferases transfer a methyl group (-CH3) from acosubstrate (donor) to a substrate molecule (acceptor), leading to the formation of a methylated molecule.[10][17] Most methyltransferases useS-adenosyl-L-methionine (SAM-e) as a donor, converting it intoS-adenosyl-L-homocysteine (SAH).[10][17] In various species, members of the methyltransferase superfamily of enzymes methylate a wide range of molecules, includingsmall molecules,proteins,nucleic acids, andlipids. These enzymes are involved in numerouscellular processes such assignaling, protein repair,chromatin regulation, andgene regulation. More than 230 families of methyltransferases have been described in variousspecies.[10][19]
This specific protein, histamineN-methyltransferase, is found invertebrates, includingmammals, birds, reptiles,amphibians, and fishes, but not ininvertebrates and plants.[9][20][21]
Thecomplementary DNA (cDNA) ofHnmt was initially cloned from a rat kidney and has since been cloned from human, mouse, and guinea pig sources.[9] Human HNMT shares 55.37% similarity with that ofzebrafish, 86.76% with that of mouse, 90.53% with that of dog, and 99.54% with that ofchimpanzee.[20][22] Moreover,expressed sequence tags from cow, pig, and gorilla, as well asgenome survey sequences frompufferfish, also exhibit strong similarity to human HNMT, suggesting that it is a highly conserved protein among vertebrates.[16] To understand the role of histamineN-methyltransferase in brain function, researchers have studiedHnmt-deficient (knockout) mice, that were genetically modified to have theHnmt gene "knocked out", i.e., deactivated.[23][24] 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 thatHNMT genetic variations in humans could be linked to brain disorders.
On subcellular distribution, histamineN-methyltransferase protein in humans is mainly localized to thenucleoplasm (which is anorganelle, i.e., a subunit of a cell) andcytosol (which is the intracellular fluid, i.e., a fluid insidecells). In addition, it is localized to thecentrosome (another organelle).[25]
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.[26]
The function of the HNMT enzyme ishistamine metabolism by ways ofNτ-methylation usingS-adenosyl-L-methionine (SAM-e) as the methyl donor, producingNτ-methylhistamine, which, unless excreted, can be further processed bymonoamine oxidase B (MAOB) or bydiamine oxidase (DAO). Methylated histaminemetabolites are excreted with urine.[16][17]
Inmammals, there are two main ways to inactivate histamine by metabolism: one is through a process calledoxidative deamination, which involves the enzymediamine oxidase (DAO) produced by theAOC1 gene, and the other is through a process calledNτ-methylation, which involves the enzymeN-methyltransferase.[29] 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).[30][31][32][33]
HNMT and DAO are two enzymes that play distinct roles in histamine metabolism. DAO is primarily responsible for metabolizing histamine inextracellular (outside cells) fluids,[34][35][36] which include interstitial fluid[37][38] (fluid surrounding cells) and blood plasma.[39] Such histamine can beexogenous (from food or intestinal flora) orendogenous (released from granules ofmast cells andbasophils, such as during allergic reactions).[35] DAO is predominantly expressed in the cells of theintestinal epithelium andplacenta but not in thecentral nervous system (CNS).[36][40] 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 thecytosol, which is the fluid inside cells. Histamine is required to be carried into the cytosol through transporters[41] such asplasma membrane monoamine transporter (SLC29A4) ororganic cation transporter 3 (SLC22A3). HNMT enzyme is found in cells of diverse tissues:neurons andglia, brain,kidneys,liver,bronchi,large intestine,ovary,prostate,spinal cord,spleen, andtrachea, etc.[28][42][40] While DAO is primarily found in theintestinal 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 otherbiogenic amines—substances, produced by a life form (like a bacteria or an animal) that has anamine functional group (−NH2).[15][43] The examples of biogenic amines besides histamine that DAO can metabolize areputrescine andcadaverine;[44] still, DAO has a preference for histamine.[45] Both DAO and HNMT exhibit comparableaffinities toward histamine.[40][46]
In the brain of mammals, histamine takes part inhistaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between theneurons—the nerve cells.[47] Histamineneurotransmitter activity is controlled by HNMT, since DAO is not present in the CNS.[5] Consequently, the deactivation of histamine via HNMT represents the sole mechanism for endingneurotransmission within the mammalian CNS.[28] This highlights the key role of HNMT for the histamine system of the brain and the brain function in general.[28]
Histamine has important roles in human physiology as both ahormone and aneurotransmitter. 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, anduterus.[48][49] As a neurotransmitter, histamine promotesarousal and regulates appetite and the sleep-wake cycle.[50][51][47] It also affectsvasodilation, fluid production in tissues like the nose and eyes,gastric acid secretion, sexual function, and immune responses.[48][49]
HNMT is the only enzyme in the human body responsible for metabolizing histamine within theCNS, playing a role in brain function.[23][41]
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,[48][49] which inhibitsHNMTgene expression in anegative feedback loop.[52] 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 theCNS, ending its neurotransmitter activity.[48][49]
HNMT also plays a role in the airway response to harmful particles,[53] which is the body's physiological reaction to immune allergens, bacteria, or viruses in the respiratory system. Histamine is stored in granules inmast cells,basophils, and in thesynaptic vesicles ofhistaminergic 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.[54][55]
Histamine intolerance is a presumed set of adverse reactions to ingestedhistamine in food believed to be associated with flawed activity of DAO and HNMT enzymes.[56] This set of reactions include cutaneous reactions (such asitching,flushing andedema), gastrointestinal symptoms (such asabdominal pain anddiarrhea), respiratory symptoms (such asrunny nose andnasal congestion), and neurological symptoms (such asdizziness and headache).[56][41] However, this link between DAO and HNMT enzymes and adverse reactions to ingestedhistamine in food is not shared by mainstream science due to insufficient evidence.[56] 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.[56] Despite extensive research, there are no definitive, objective measures or indicators that could unambiguously define histamine intolerance as a distinct medical condition.[56]
The activity of HNMT, unlike that of DAO, cannot be measured by blood (serum) analysis.[13][57]
Organs that produce DAO continuously release it into the bloodstream. DAO is stored invesicular structures associated with the plasma membrane in epithelial cells.[40] 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.[40]
There is a genetic variant, registered inthe Single Nucleotide Polymorphism database (dbSNP) as rs11558538, found in 10% of the population worldwide,[58] which means that the Tallele presents at position 314 ofHNMT instead of a usual C allele (c.314C>T). This variant causes the protein to be synthesized withthreonine (Thr) replaced withisoleucine (Ile) at position 105 (p.Thr105Ile, T105I). This variant is described asloss-of-function allele reducing HNMT activity, and is associated with diseases such as asthma,allergic rhinitis, andatopic eczema (atopic dermatitis). For individuals with this variant, the intake of HNMTinhibitors, which hamper enzyme activity, andhistamine liberators, which release histamine from the granules of mast cells and basophils, could potentially influence their histamine levels.[59] Still, this genetic variant is associated with a reduced risk ofParkinson's disease.[60][61][17]
Experiments involvingHnmt-knockout mice have shown that a deficiency in HNMT indeed leads to increased brain histamine concentrations, resulting in heightened aggressive behaviors and disruptedsleep-wake cycles in these mice. In humans, genetic variants that affect HNMT activity have been implicated in various brain disorders, such asParkinson's disease andattention 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 incerebrospinal fluid have been consistently reported in patients withnarcolepsy and other conditions characterized by excessive daytime sleepiness. The association betweenHNMT 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 inHNMT 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.[28]
The following substances are known to be HNMTinhibitors:amodiaquine,chloroquine,dimaprit,etoprine,metoprine,quinacrine,SKF-91488,tacrine, anddiphenhydramine.[62][63] HNMT inhibitors may increase histamine levels in peripheral tissues and aggravate conditions associated with histamine excess, such asallergic rhinitis,urticaria, andpeptic ulcer disease. As of 2024,[update] 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.[62][63]
HNMT could be a potential target for the treatment of symptoms ofmethamphetamine overdose.[64] 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.[65][66] 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 bemetoprine, which crosses the blood-brain barrier and can potentially increase brain histamine levels by inhibiting HNMT; still, as of 2024,[update] treatment of methamphetamine overdose by HNMT inhibitors is still an area of research.[64]
Nτ-methylhistamine (NτMH), also known as 1-methylhistamine, is a product ofNτ-methylation of histamine in a reaction catalyzed by the HNMT enzyme.[27][16][17]
NτMH is considered a biologically inactive metabolite of histamine.[67][68][69] NτMH is excreted in the urine and can be measured to estimate the amounts of active histamine in the body.[70] While NτMH has some biological activity on its own, it is much weaker than histamine. NτMH can bind tohistamine receptors but has a loweraffinity andefficacy 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 anantagonist 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.[71] Still, NMT, being a product in a reaction catalyzed by HNMT, may inhibit expression of HNMT in a negative feedback loop.[52]
Urinary NτMH can be measured in clinical settings whensystemic mastocytosis is suspected. Systemic mastocytosis andanaphylaxis are typically associated with at least a two-fold increase in urinary NτMH levels, which are also increased in patients takingmonoamine oxidase inhibitors and in patients on histamine-rich diets.[70]
This article incorporatespublic domain material from"HNMT HistamineN-methyltransferase".Reference Sequence collection. National Center for Biotechnology Information. Retrieved30 November 2020.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.
This article incorporates text from this source, which is in thepublic domain. This article incorporatespublic domain material from"HNMT histamine N-methyltransferase [Danio rerio (Zebrafish)] – Gene – NCBI".Reference Sequence collection.National Center for Biotechnology Information.Extracellular fluid is distributed in two major sub-compartments: interstitial fluid and plasma
This article incorporates text from this source, which is available under theCC BY 4.0 license. This article incorporatespublic domain material from"rs11558538 RefSNP Report – dbSNP – NCBI".Reference Sequence collection.National Center for Biotechnology Information.This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
