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 N^τ-methylhistamine, in a chemical reaction called N^τ-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.