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 and diamine oxidase (DAO) are the only two enzymes responsible for histamine metabolism; unlike DAO, HNMT is present 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 within the CNS, HNMT supports neural pathways related to arousal, appetite regulation, and sleep-wake cycles. 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 indicate that HNMT maintains normal brain function by regulating 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
Histamine N-methyltransferase is encoded by a single gene, called HNMT, which has been mapped to chromosome 2 in humans. Three transcript variants have been identified for this gene in humans, which produce different protein isoforms 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. Of those isoforms, only one has histamine-methylating activity. 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. HNMT does not have promoter cis-elements, such as TATA and CAAT boxes.
Protein
HNMT is a cytoplasmic protein, meaning that it operates within the cytoplasm of a cell. 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). HNMT helps regulate histamine levels by degrading histamine within the cytoplasm, ensuring proper cellular function. 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. The first domain, called the "MTase domain", contains the active site where methylation occurs. The domain 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. 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. This region includes an anti-parallel beta sheet along with additional alpha helices and 310 helices.
Species Histamine N-methyltransferase belongs to methyltransferases, a superfamily of enzymes present in every life form, including archaeans. 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. To carry out methylation, methyltransferases transfer a methyl group (-CH3) from a cosubstrate (donor) to a substrate molecule (acceptor), leading to the formation of a methylated molecule. Most methyltransferases use S-adenosyl-L-methionine (SAM-e) as a donor, converting it into S-adenosyl-L-homocysteine (SAH). 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. This specific protein, histamine N-methyltransferase, is found in vertebrates, including mammals, birds, reptiles, amphibians, and fishes, but not in invertebrates and plants. 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. 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. 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. 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. Disrupting the gene led to a marked rise in histamine levels in the mouse brain, showing the gene's role in the brain's histamine system and suggesting that HNMT genetic variations in humans could be linked to brain disorders.
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