Histamine ''N''-methyltransferase (HNMT, HMT) is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

involved in the

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...

. It is one of two enzymes involved in the metabolism of

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

, the other being

diamine oxidase Diamine oxidase (DAO), also known "amine oxidase, copper-containing, 1" (AOC1), formerly called histaminase, is an enzyme () involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermid ...

(DAO). HNMT catalyzes the

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

of histamine in the presence of ''S''-adenosylmethionine (SAM-e) forming ''N''-methylhistamine. The HNMT enzyme is present in most body tissues but is not present in serum. Histamine ''N''-methyltransferase is encoded by a single gene, ''HNMT'', which in humans has been mapped to chromosome 2.

Function

The function of the HNMT enzyme is

metabolism by ways of ''N^τ''-methylation using

SAM-e ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

as the methyl donor, producing ''N''-methylhistamine, which, unless excreted, can be further processed by

monoamine oxidase B Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. ...

(MAOB) or by

DAO Dao, Dão or DAO may refer to: * Tao (Chinese: "The Way" 道), a philosophical concept * Dao (Chinese sword) (刀), a type of Chinese sword * Dao (Naga sword), a weapon and a tool of Naga people People and language * Yao people, a minority ethni ...

. Methylated histamine metabolites are excreted with urine. In

, histamine is metabolized by two major pathways:

oxidative deamination Oxidative deamination is a form of deamination that generates α-keto acids and other oxidized products from amine-containing compounds, and occurs primarily in the liver. Oxidative deamination is stereospecific, meaning it contains different stere ...

via

, encoded by the ''AOC1'' gene, and ''N^τ''-methylation via HNMT, encoded by the ''HNMT'' gene. In brain of mammals histamine

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

activity is controlled by ''N^τ''-methylation since DAO is not present in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. As about the biologic species, the HNMT enzyme is found in

vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

, including

birds Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

reptiles Reptiles, as most commonly defined are the animals in the Class (biology), class Reptilia ( ), a paraphyletic grouping comprising all sauropsid, sauropsids except birds. Living reptiles comprise turtles, crocodilians, Squamata, squamates (lizar ...

and

amphibian Amphibians are tetrapod, four-limbed and ectothermic vertebrates of the Class (biology), class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terres ...

, but not in

invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

and

plants Plants are predominantly Photosynthesis, photosynthetic eukaryotes of the Kingdom (biology), kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all curr ...

. The HNMT enzyme resides in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

intracellular fluid. Whereas DAO metabolizes extracellular free histamine, be it either

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogeno ...

came with food or mostly

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

released from granules of

mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

and basophils as a result of

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

, in view of the fact that DAO is mainly expressed in the cells of

intestinal epithelium The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functi ...

, HNMT is involved in metabolism of the persistently present intracellular primarily endogenous histamine, mainly in

kidneys The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

and

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

, but also in

bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...

large intestine The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being r ...

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...

prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

trachea The trachea, also known as the windpipe, is a Cartilage, cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends ...

and peripheral tissues. In the case of flawed HNMT activity, the organs which are most affected are brain, liver and mucous membrane of bronchus. Consequently, flawed HNMT activity leads to chronic forms of

histamine intolerance Histamine intolerance, sometimes called histaminosis, is an over-accumulation of dietary histamine in the human body. Histamine intolerance is sometimes informally called an allergy; however, the intolerance is technically caused by the gradual ac ...

. For instance, the main symptoms of histamine intolerance within the nervous system are

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

, myoclonic twitching and

unrest Unrest, also called disaffection, is a sociological phenomenon, including: * Civil unrest * Civil disorder * Domestic terrorism * Industrial unrest * Labor unrest * Rebellion * Riot * Strike action * State of emergency Notable historical instance ...

. Overall, the symptoms of flawed HNMT activity are typical of symptoms of histamine intolerance, including

allergic rhinitis Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, i ...

urticaria Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...

(

hives Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...

), and

peptic ulcer disease Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...

Measurements

Whereas DAO comes to the blood stream from the organs where it is expressed (small bowel and large intestine ascendens, kidney, etc.) in a continuous manner and stored in plasma membrane-associated vesicular structures in epithelial cells, and therefore serum DAO activity can be reliably measured while diagnosing histamine intolerance, measurement of intracellular HNMT which presents primarily in the cells of the internal organs, like the liver, is troublesome, so diagnosis is done, as a rule, indirectly, through testing for genetic variants. Although the consequences of flawed DAO activity are often periodic, the consequences of flawed HNMT activity occur immediately, and the symptoms also immediately appear, for example, after meals.

Genetic variants

The most studied genetic variant is T allele at rs11558538 (c.314C>T, p.Thr105Ile), a loss-of-function allele reducing HNMT activity and associated with diseases, typical for histamine intolerance, such as asthma,

and

atopic eczema Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin (dermatitis). It results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens over time ...

(

atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin (dermatitis). It results in puritis, itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens o ...

). Therefore the owners of this variant should avoid intake of HNMT inhibitors which hamper enzyme activity, and also should avoid intake of

histamine liberators Histamines are organic compounds that primarily function as the human body's immune responses as well as the for regulation of many physiological functions. Since their discovery in 1910, histamines have been known to trigger inflammatory responses ...

which release histamine from granules of mast cells and basophils. In a study of 48 adults, median enzyme activity was significantly lower in subjects with the CT or TT

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

than in those with the

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

CC genotype (485 versus 631 U/mL of red blood cells). In another study of 195 subjects, the C314T variant also showed an association with serum

Interleukin-8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...

(IL-8) levels — individuals with the CT or TT genotype had lower levels of IL-8 ( versus 2.1) and higher levels of histamine ( versus ) in comparison with individuals with the CC genotype. The carriers of CT and TT genotypes were merged in one group in this study because there were too few participants with TT to form a group large enough to make statistical relevance, therefore CT and TT might have different enzyme activity which is not yet studied . This effect may indicate that there may be a link between this genetic variant and inflammation. Although the relationship between histamine and IL-8 has not been fully studied , it is known that histamine can increase the expression of IL-8 through H1 receptors ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' and enhance the release of IL-8 in different cell types. Other genetic variants have been also identified to affect enzyme function. The rs1050891 (939A>G, 3′-UTR) variant leads to increased enzymatic activity (

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...

stability), while rs758252808 (c.179G>A, p.Gly60Asp) and rs745756308 (c.623T>C, p. Leu208Pro) lead to decreased enzymatic activity.

Inhibitors

The following substances are known to be HNMT inhibitors:

amodiaquine Amodiaquine (ADQ) is a medication used to treat malaria, including ''Plasmodium falciparum'' malaria when uncomplicated. It is recommended to be given with artesunate to reduce the risk of resistance. Due to the risk of rare but serious side effec ...

chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...

, dimaprit, etoprine, metoprine,

quinacrine Mepacrine, also called quinacrine or by the trade name Atabrine, is a medication with several uses. It is related to chloroquine and mefloquine. Although formerly available from compounding pharmacies, as of August 2020 it is unavailable in th ...

, SKF-91488,

tacrine Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed un ...

and

diphenhydramine Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into a vein ...

. HNMT inhibitors may increase histamine levels in peripheral tissues and exacerbate histamine-related diseases, such as

, and

. However, the effect of HNMT inhibitors on brain function is not yet fully understood. Some studies suggest that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.

References

External links