Histamine N-methyltransferase
Histamine N-methyltransferase | |||||||||
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Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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histamine N-methyltransferase | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process |
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Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 2: 137.96 – 138.02 Mb | Chr 2: 23.89 – 23.94 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Histamine N-methyltransferase (HNMT) is a
Specifically, HNMT transfers a methyl (CH3) group from
Research on knockout 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; still, as of 2024,[update] it remains unclear whether alterations in HNMT are primary causes or secondary effects of these conditions.
Gene
Histamine N-methyltransferase is encoded by a single gene, called HNMT, which has been mapped to chromosome 2 in humans.[5]
Three transcript variants have been identified for this gene in humans, which produce different protein isoforms[6][5] 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.[7][8] Of those isoforms, only one has histamine-methylating activity.[6]
In the human genome, six exons from the 50-
Protein
The
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.[12][13]
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
Species
Histamine N-methyltransferase belongs to methyltransferases, a
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][13][15]
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.
This specific protein, histamine N-methyltransferase, is found in
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.[9] 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.[18][19] 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.[12] To understand the role of histamine N-methyltransferase in brain function, researchers have studied Hnmt-deficient (knockout) mice.[20][17][21] 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.[17]
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).[22]
In humans, the protein is present in many tissues and is most abundantly expressed in the brain,
Function
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.[12][13][11]
In mammals, histamine is metabolized by two major pathways:
HNMT and DAO are two enzymes that play distinct roles in histamine metabolism. DAO is primarily responsible for metabolizing histamine in
In the brain of mammals, histamine neurotransmitter 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 ending neurotransmission within the mammalian CNS.[25] This highlights the key role of HNMT for the histamine system of the brain and the brain function in general.[17]
Clinical significance
Role in health
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. As a neurotransmitter, histamine promotes arousal and regulates the sleep-wake cycle. It also affects vasodilation, fluid production in tissues like the nose and eyes, gastric acid secretion, sexual function, and immune responses.[37][38]
HNMT plays a crucial 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,[37][38] which inhibits HNMT gene expression in a negative feedback loop.[39] 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.[37][38]
HNMT also plays a role in the airway response to harmful particles,[40] 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.[41][42]
Histamine intolerance
Activity measurements
The activity of HNMT, unlike that of DAO, cannot be measured by blood (serum) analysis.[49][50][51]
Organs that produce DAO continuously release it into the bloodstream. DAO is stored in
Genetic variants
There is a genetic variant, registered in the Single Nucleotide Polymorphism database (dbSNP) as rs11558538, found in 10% of the population worldwide,[52] 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, typical for histamine intolerance, 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.[53][54] Still, this genetic variant is associated with a reduced risk of Parkinson's disease.[55][56][13]
Experiments involving Hnmt-
Inhibitors
The following substances are known to be HNMT
Methamphetamine overdose
HNMT could be a potential target for the treatment of symptoms of methamphetamine overdose.[60] 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.[61][62] 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,[update] treatment of methamphetamine overdose by HNMT inhibitors is still an area of research.[60]
Nτ-methylhistamine
Nτ-methylhistamine (NMH), also known as 1-methylhistamine, is a product of Nτ-methylation of histamine in a reaction catalyzed by the HNMT enzyme.[24][12][13]
NMH is considered a biologically inactive metabolite of histamine.
Urinary NMH can be measured in clinical settings when
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000150540 - Ensembl, May 2017
- ^ a b c 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.
- ^ a b c This article incorporates public domain material from "HNMT Histamine N-methyltransferase". Reference Sequence collection. National Center for Biotechnology Information. Retrieved 30 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.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
External links
- Histamine+N-Methyltransferase at the U.S. 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