HNMT

Histamine N-methyltransferase (HNMT) is a cytosolic methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to histamine, generating Nτ-methylhistamine and serving as a major pathway for intracellular histamine inactivation^[1]. HNMT is highly expressed in the central nervous system, where it functions as the principal mechanism controlling neuronal histamine turnover and termination of histaminergic neurotransmission^[1][2][3]. Mechanistically, HNMT regulates histamine-dependent signaling networks involved in arousal, sleep-wake regulation, cognition, and neuroimmune responses through enzymatic clearance of intracellular histamine^[1][2]. In disease contexts, genetic disruption or loss-of-function variants of HNMT increase brain histamine concentrations and have been associated with intellectual disability, attention-deficit/hyperactivity disorder, Parkinson’s disease, asthma, and atopic disorders, supporting a critical role for histamine homeostasis in neurological and inflammatory phenotypes^[2][4][5]. Compared with the related histamine-degrading enzyme diamine oxidase (DAO), which primarily metabolizes extracellular histamine in peripheral tissues, HNMT preferentially regulates intracellular histamine and represents the dominant histamine-catabolic pathway in the brain^[3][6]. Therefore, HNMT provides a distinct experimental target for investigating central histaminergic signaling, neurobehavioral regulation, and histamine-associated disease mechanisms^[1][2]. For research applications, pharmacological HNMT inhibition has been used to elevate brain histamine levels in experimental models and to evaluate the physiological consequences of altered histamine metabolism in the central nervous system^[1][2].