The function of the HNMT enzyme is histamine metabolism by ways of N-methylation using S-adenosyl--methionine (SAM-e) as the methyl donor, producing N-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.
In mammals, there are two main ways to inactivate histamine by metabolism: one is through a process called oxidative deamination, which involves the enzyme diamine oxidase (DAO) produced by the AOC1 gene, and the other is through a process called N-methylation, which involves the enzyme N-methyltransferase. In the context of biochemistry, inactivation by metabolism refers to the process where a substance, such as a hormone, is converted into a form that is no longer active or effective (inactivation), via a process where the substance is chemically altered (metabolism).
HNMT and DAO are two enzymes that play distinct roles in histamine metabolism. DAO is primarily responsible for metabolizing histamine in extracellular (outside cells) fluids, which include interstitial fluid (fluid surrounding cells) and blood plasma. Such histamine can be exogenous (from food or intestinal flora) or endogenous (released from granules of mast cells and basophils, such as during allergic reactions). DAO is predominantly expressed in the cells of the intestinal epithelium and placenta but not in the central nervous system (CNS). In contrast, HNMT is expressed in CNS and involved in the metabolism of intracellular (inside cells) histamine, which is primarily endogenous and persistently present. HNMT operates in the cytosol, which is the fluid inside cells. Histamine is required to be carried into the cytosol through transporters such as plasma membrane monoamine transporter (SLC29A4) or organic cation transporter 3 (SLC22A3). HNMT enzyme is found in cells of diverse tissues: neurons and glia, brain, kidneys, liver, bronchi, large intestine, ovary, prostate, spinal cord, spleen, and trachea, etc. While DAO is primarily found in the intestinal epithelium, HNMT is present in a wider range of tissues throughout the body. This difference in location also requires different transport mechanisms for histamine to reach each enzyme, reflecting the distinct roles of these enzymes in histamine metabolism. Another distinction between HNMT and DAO lies in their substrate specificity. While HNMT has a strong preference for histamine, DAO can metabolize other biogenic amines—substances, produced by a life form (like a bacteria or an animal) that has an amine functional group (−NH). The examples of biogenic amines besides histamine that DAO can metabolize are putrescine and cadaverine; still, DAO has a preference for histamine. Both DAO and HNMT exhibit comparable affinities toward histamine.
In the brain of mammals, histamine takes part in histaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between the neurons—the nerve cells. Histamine neurotransmitter activity is controlled by HNMT, since DAO is not present in the CNS. Consequently, the deactivation of histamine via HNMT represents the sole mechanism for ending neurotransmission within the mammalian CNS. This highlights the key role of HNMT for the histamine system of the brain and the brain function in general.