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Histamine N-methyltransferase
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.
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.
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.
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Histamine N-methyltransferase
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.
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.
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.