Diamine oxidase

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Diamine oxidase
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Diamine oxidase dimer, Human
Identifiers
EC no. 1.4.3.22
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MetaCyc metabolic pathway
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Diamine oxidase (DAO), also known "amine oxidase, copper-containing, 1" (AOC1), formerly called histaminase, [1] is an enzyme (EC 1.4.3.22) involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermidine. The enzyme belongs to the amine oxidase (copper-containing) (AOC) family of amine oxidase enzymes.

Contents

The enzyme is expressed in bilateria, a biological group of animals. The enzyme is encoded by the AOC1 gene. This gene is highly conserved across the bilateria group which includes mammals, birds, reptiles, fish and insects, to name a few.

Chemical activity

DAO catalyzes the oxidative deamination of polyamines, such as histamine and putrescine, to produce aminoaldehydes, hydrogen peroxide, and ammonia.

DAO metabolizes histamine into imidazole-4-acetaldehyde.

Biological role

DAO is involved in the physiology of digestion and other physiological processes, such as inflammation, immune response, and wound healing. Dysfunction of DAO has been associated with various diseases, including allergies, autoimmune disorders, and cancer. DAO also plays a role in healthy pregnancy in placental mammals.

In case of a shortage or low enzymatic activity of diamine oxidase in the human body, it may appear as an allergy or histamine intolerance. [2] [3] [4]

Expression

In placental mammals, including humans, the highest levels of DAO expression are observed in the digestive tract (intestinal mucosa) and the placenta. DAO expression is also observed in kidney of various species.

DAO is also expressed in eosinophils. [5] [6]

The role in human pregnancy

In humans, a certain subtype of cells of the placenta, namely the extravillous trophoblasts, express the enzyme and secrete it into the blood stream of a pregnant woman. [7]

During pregnancy, DAO plays a crucial role in maintaining fetal growth and development by regulating histamine levels. [7] DAO levels in the blood circulation increases vastly in pregnant women suggesting a protective mechanism against adverse histamine. [8] Histamine is a potent vasodilator and can cause uterine contractions, which can lead to premature labor. DAO in the placenta breaks down histamine to prevent its accumulation and maintain a healthy pregnancy. Low levels of DAO in the placenta may contribute to preeclampsia, a pregnancy-related disorder characterized by mother's high blood pressure and damage to mother's organs such as the liver and kidneys; the baby may also be affected if the condition is severe or left untreated, but it is not the primary target of the disorder.

Lowered diamine oxidase values in maternal blood in early pregnancy might be an indication for trophoblast-related pregnancy disorders like early-onset preeclampsia. [8]

Supplementation

Exogenous DAO (supplements) are being studied as complementary treatment [9] for the relief of symptoms associated with histamine intolerance, and for the relief of other conditions, such as migraine [10] or fibromyalgia. [11] However, the results are inconclusive because studies to date have involved small study populations and short intervention periods. [12] [13] [14]

In the United States, DAO supplements are available over the counter but are not FDA-approved. [15]

In Europe, two investigations, financially backed by the manufacturer of the oral DAO supplementation, have posited that DAO supplementation could alleviate patient symptoms. [16] The first study sought to "objectify and quantify histamine-associated symptoms and to analyze whether oral administration of the histamine-degrading enzyme DAO caused a reduction of symptoms". [16] In this study, neither major nor minor symptoms could be replicated in 39 patients who initially responded to an open challenge with 75 mg histamine in peppermint tea, using a double-blind, placebo-controlled challenge. [16] Consequently, the primary endpoint of the study was not achieved, and the basis for the authors' conclusion that DAO supplementation intake resulted in a "statistically significant reduction in symptoms" remains unclear. The second study was purely observational, lacking a control group: it compared symptomatology with and without DAO use in 28 patients. [16] The chosen design was not suitable to demonstrate causal effects and carried a high risk of attributing placebo effects. [16] The effectiveness of DAO supplementation has not been scientifically validated and is not recommended by the medical associations in Germany, Austria and Switzerland. [16]

Research directions

DAO is related on possible links to migraine conditions. During migraine episodes, there is a noted elevation in the plasma concentrations of both calcitonin gene-related peptide (CGRP) and histamine. These substances are known for their potent vasodilatory effects and have been observed to mutually stimulate each other's release within the trigeminovascular system, potentially contributing to the onset of migraines, so that individuals with genetic variants in the DAO gene often experience migraines when consuming a diet high in histamine. As such, exploring the functional interplay between exogenous histamine and CGRP could provide valuable insights into the mechanisms underlying diet-induced migraines. This area of research continues to be actively investigated. [17]

Related Research Articles

<span class="mw-page-title-main">Placenta</span> Organ that connects the fetus to the uterine wall

The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Histamine</span> Organic compound involved in immune responses

Histamine is an organic nitrogenous compound involved in local immune responses communication, 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 in 1910, it has been considered a local hormone (autocoid) because it lacks the classic endocrine glands to secrete it; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

<span class="mw-page-title-main">Pre-eclampsia</span> Hypertension occurring during pregnancy

Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances. Pre-eclampsia increases the risk of undesirable as well as lethal outcomes for both the mother and the fetus including preterm labor. If left untreated, it may result in seizures at which point it is known as eclampsia.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

HELLP syndrome is a complication of pregnancy; the acronym stands for hemolysis, elevated liver enzymes, and low platelet count. It usually begins during the last three months of pregnancy or shortly after childbirth. Symptoms may include feeling tired, retaining fluid, headache, nausea, upper right abdominal pain, blurry vision, nosebleeds, and seizures. Complications may include disseminated intravascular coagulation, placental abruption, and kidney failure.

<span class="mw-page-title-main">Gestational hypertension</span> Medical condition

Gestational hypertension or pregnancy-induced hypertension (PIH) is the development of new hypertension in a pregnant woman after 20 weeks' gestation without the presence of protein in the urine or other signs of pre-eclampsia. Gestational hypertension is defined as having a blood pressure greater than 140/90 on two occasions at least 6 hours apart.

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Histamine H<sub>1</sub> receptor Histamine receptor

The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate (IP3) signalling pathway. Antihistamines, which act on this receptor, are used as anti-allergy drugs. The crystal structure of the receptor has been determined (shown on the right/below) and used to discover new histamine H1 receptor ligands in structure-based virtual screening studies.

Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). In such neurons, release of these pro-inflammatory mediators is thought to be triggered by the activation of ion channels that are the principal detectors of noxious environmental stimuli. In particular, the heat/capsaicin receptor TRPV1 and the irritant/wasabi receptor TRPA1. TRPA1 channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established.

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Histamine <i>N</i>-methyltransferase Mammalian enzyme involved in the metabolism of histamine

Histamine N-methyltransferase (HNMT) is a cytoplasmic protein encoded by the HNMT gene in humans. It belongs to the methyltransferases superfamily of enzymes and plays a crucial role in the inactivation of histamine, a biogenic amine involved in various physiological processes. Methyltransferases are present in every life form including archaeans, with 230 families of methyltransferases found across species.

<span class="mw-page-title-main">HLA-G</span>

HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.

<span class="mw-page-title-main">Amine oxidase (copper-containing)</span>

Amine oxidase (copper-containing) (AOC) (EC 1.4.3.21 and EC 1.4.3.22; formerly EC 1.4.3.6) is a family of amine oxidase enzymes which includes both primary-amine oxidase and diamine oxidase; these enzymes catalyze the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. They act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor:

<span class="mw-page-title-main">Placental growth factor</span> Protein-coding gene in the species Homo sapiens

Placental growth factor(PlGF) is a protein that in humans is encoded by the PGF gene.

<span class="mw-page-title-main">Placental disease</span> Medical condition

A placental disease is any disease, disorder, or pathology of the placenta.

Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.

Histamine intolerance is a presumed set of adverse reactions to ingested histamine in food. The mainstream theory accepts that there may exist adverse reactions to ingested histamine, but does not recognize histamine intolerance as a separate condition that can be diagnosed. There is a common suspicion that ingested histamine in persons with deficiencies in the enzymes that metabolize histamine may be responsible for various non-specific health complaints, which some individuals categorize as histamine intolerance, still, histamine intolerance is not recognized as an explicit medical condition with that name in the International Classification of Diseases (ICD) Edition 11, or any previous edition. The scientific proof that supports the idea that eating food containing histamine can cause health problems is currently limited and not consistent.

<span class="mw-page-title-main">Imidazole-4-acetaldehyde</span> Chemical compound

Imidazole-4-acetaldehyde is a metabolite of histamine in biological species.

References

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