Diamine oxidase

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Diamine oxidase
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Diamine oxidase dimer, Human
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EC no. 1.4.3.22
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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

Histamine metabolites

Histamine, a biogenic amine, undergoes metabolism through three distinct enzymatic pathways: [2]

  1. The first pathway (see the reaction illustrated below) involves the deamination of histamine by the enzyme diamine oxidase to form imidazoleacetic acid. [2]
  2. In the second pathway, histamine is metabolized into Nτ-methylhistamine (also known as 1-Methylhistamine), which also has some biological activity, albeit much weaker than that of histamine. [3] Still, NMT, being a product in a reaction catalyzed by HNMT, may inhibit expression of HNMT in a negative feedback loop. [4] This reaction is Nτ-methylation of histamine by the histamine N-methyltransferase (HNMT) enzyme. The Nτ-methylhistamine, unless excreted by the kindney, is subsequently oxidized into Nτ-methylimidazoleacetic acid (NτMIAA) by the enzyme monoamine oxidase (MAO). This two-step process effectively reduces the activity of histamine in the body and is particularly important for quick deactivation of histamine in the brain. [2]
  3. The third pathway involves the acetylation of histamine by an acetylase to form 4-(-acetylaminoethyl)imidazole. However, it’s important to note that this pathway is found exclusively in enterobacteria and has not been identified in mammals. This suggests a unique metabolic pathway for histamine in these bacteria. [2]

These pathways highlight the complex and varied mechanisms through which histamine is metabolized in different organisms. Understanding these pathways is crucial for biomedical professionals as it can provide insights into the regulation of histamine levels and its role in various physiological and pathological processes. [2] DAO catalyzes the oxidative deamination of polyamines, such as histamine and putrescine, to produce aminoaldehydes, [2] hydrogen peroxide, [2] and ammonia. [2]

Reaction catalyzed by DAO

DAO metabolizes histamine into imidazole-4-acetaldehyde:

R−CH2−NH2 + H2O + O2 → R−CHO + NH3 + H2O2

Imidazole-4-acetaldehyde is then further oxidized by a NAD-dependent aldehyde dehydrogenase, leading to imidazole-4-acetic acid. [5]

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. [6] [7] [8]

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. [9] [10]

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. [11]

During pregnancy, DAO plays a crucial role in maintaining fetal growth and development by regulating histamine levels. [11] DAO levels in the blood circulation increases vastly in pregnant women suggesting a protective mechanism against adverse histamine. [12] 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. [12]

Supplementation

Exogenous DAO (supplements) are being studied as complementary treatment [13] for the relief of symptoms associated with histamine intolerance, and for the relief of other conditions, such as migraine [14] or fibromyalgia. [15] However, the results are inconclusive because studies to date have involved small study populations and short intervention periods. [16] [17] [18]

In the United States, DAO supplements are available over the counter but are not FDA-approved. [19]

In Europe, two investigations, financially backed by the manufacturer of the oral DAO supplementation, have posited that DAO supplementation could alleviate patient symptoms. [20] 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". [20] 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. [20] 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. [20] The chosen design was not suitable to demonstrate causal effects and carried a high risk of attributing placebo effects. [20] The effectiveness of DAO supplementation has not been scientifically validated and is not recommended by the medical associations in Germany, Austria and Switzerland. [20]

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. [21]

Related Research Articles

<span class="mw-page-title-main">Monoamine oxidase</span> Family of enzymes

Monoamine oxidases (MAO) are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first such enzyme was discovered in 1928 by Mary Bernheim in the liver and was named tyramine oxidase. The MAOs belong to the protein family of flavin-containing amine oxidoreductases.

<span class="mw-page-title-main">Putrescine</span> Foul-smelling organic chemical compound

Putrescine is an organic compound with the formula (CH2)4(NH2)2. It is a colorless solid that melts near room temperature. It is classified as a diamine. Together with cadaverine, it is largely responsible for the foul odor of putrefying flesh, but also contributes to other unpleasant odors.

<span class="mw-page-title-main">Histidine</span> Chemical compound

Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the deprotonated –COO− form under biological conditions), and an imidazole side chain (which is partially protonated), classifying it as a positively charged amino acid at physiological pH. Initially thought essential only for infants, it has now been shown in longer-term studies to be essential for adults also. It is encoded by the codons CAU and CAC.

<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. Discovered in 1910, histamine has been considered a local hormone (autocoid) because it's produced without involvement of the classic endocrine glands; 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 new onset of high blood pressure and often a significant amount of protein in the urine or by the new onset of high blood pressure along with significant end-organ damage, with or without the proteinuria. 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.

<span class="mw-page-title-main">Tyramine</span> Chemical compound

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

Food intolerance is a detrimental reaction, often delayed, to a food, beverage, food additive, or compound found in foods that produces symptoms in one or more body organs and systems, but generally refers to reactions other than food allergy. Food hypersensitivity is used to refer broadly to both food intolerances and food allergies.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

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.

<span class="mw-page-title-main">Calcitonin gene-related peptide</span> Peptide hormone in animals

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

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

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.

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

<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">PLAC1</span> Protein-coding gene in the species Homo sapiens

Placenta-specific protein 1 is a small, secreted cell surface protein encoded on the X-chromosome by the PLAC1 gene. Since its discovery in 1999, PLAC1 has been found to play a role in placental development and maintenance, several gestational disorders including preeclampsia, fetal development and a large number of cancers.

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

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

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">1-Methylhistamine</span> Chemical compound

1-Methylhistamine is a metabolite of histamine.

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

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

γ-Aminobutyraldehyde, also known as 4-aminobutanal, 4-aminobutyraldehyde, or GABA aldehyde, is a metabolite of putrescine and a biological precursor of γ-aminobutyric acid (GABA). It can be converted into GABA by the actions of diamine oxidase (DAO) and aminobutyraldehyde dehydrogenase (ABALDH). Putrescine is converted into ABAL via monoamine oxidase B (MAO-B). However, biosynthesis of GABA from polyamines like putrescine is a minor metabolic pathway in the brain.

References

  1. ↑ Wolvekamp MC, de Bruin RW (1994). "Diamine oxidase: an overview of historical, biochemical and functional aspects". Digestive Diseases. 12 (1): 2–14. doi:10.1159/000171432. PMID   8200121.
  2. 1 2 3 4 5 6 7 8 Keyzer J, Wolthers B, Breukelman H, Kauffman H, De Monchy J (1982). "Determination of Nτ-methylimidazoleacetic acid (A histamine metabolite) in urine by gas chromatography using nitrogen-phosphorus detection". Clinica Chimica Acta. 121 (3): 379–387. doi:10.1016/0009-8981(82)90247-9. PMID   6955073.
  3. ↑ Mohammed T (2010). "Biological and Pharmacological Aspects of Histamine Receptors and Their Ligands". Biomedical Aspects of Histamine. Springer. pp. 61–100. doi:10.1007/978-90-481-9349-3_4. ISBN   978-90-481-9348-6.
  4. ↑ Peters LJ, Kovacic JP (2009). "Histamine: Metabolism, physiology, and pathophysiology with applications in veterinary medicine". Journal of Veterinary Emergency and Critical Care. 19 (4): 311–328. doi:10.1111/j.1476-4431.2009.00434.x. PMID   25164630.
  5. ↑ Bähre H, Kaever V (2017). "Analytical Methods for the Quantification of Histamine and Histamine Metabolites". Handbook of Experimental Pharmacology. 241: 3–19. doi:10.1007/164_2017_22. ISBN   978-3-319-58192-7. PMID   28321587.
  6. ↑ Arih K, Đorđević N, Košnik M, Rijavec M (October 2023). "Evaluation of Serum Diamine Oxidase as a Diagnostic Test for Histamine Intolerance". Nutrients. 15 (19): 4246. doi: 10.3390/nu15194246 . PMC   10574399 . PMID   37836530.
  7. ↑ Manzotti G, Breda D, Di Gioacchino M, Burastero SE (March 2016). "Serum diamine oxidase activity in patients with histamine intolerance". International Journal of Immunopathology and Pharmacology. 29 (1): 105–11. doi:10.1177/0394632015617170. PMC   5806734 . PMID   26574488.
  8. ↑ Music E, Silar M, Korosec P, Kosnik M, Rijavec M (2011). "Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance". Clinical and Translational Allergy. 1 (Suppl 1): 115. doi: 10.1186/2045-7022-1-S1-P115 . PMC   3354134 .
  9. ↑ Zeiger RS, Colten HR (February 1977). "Histaminase release from human eosinophils". Journal of Immunology. 118 (2): 540–3. doi: 10.4049/jimmunol.118.2.540 . PMID   402420. S2CID   36128339. Archived from the original on 8 March 2024. Retrieved 2 July 2016.
  10. ↑ Agúndez JA, Ayuso P, Cornejo-García JA, Blanca M, Torres MJ, Doña I, et al. (2012). "The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs". PLOS ONE. 7 (11): e47571. Bibcode:2012PLoSO...747571A. doi: 10.1371/journal.pone.0047571 . PMC   3495953 . PMID   23152756.
  11. 1 2 Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N (2008). "Effects of histamine and diamine oxidase activities on pregnancy: a critical review". Hum Reprod Update. 14 (5): 485–95. doi: 10.1093/humupd/dmn014 . PMID   18499706.
  12. 1 2 Velicky P, Windsperger K, Petroczi K, Pils S, Reiter B, Weiss T, et al. (April 2018). "Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia". Scientific Reports. 8 (1): 6342. Bibcode:2018NatSR...8.6342V. doi:10.1038/s41598-018-24652-0. PMC   5910386 . PMID   29679053.
  13. ↑ Hakl R, Litzman J (2023). "Histamine intolerance". Vnitr Lek. 69 (1): 37–40. doi: 10.36290/vnl.2023.005 . PMID   36931880. S2CID   257604532.
  14. ↑ Izquierdo-Casas J, Comas-Basté O, Latorre-Moratalla ML, Lorente-Gascón M, Duelo A, Soler-Singla L, et al. (February 2019). "Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial". Clin Nutr. 38 (1): 152–158. doi:10.1016/j.clnu.2018.01.013. hdl: 2445/162978 . PMID   29475774. S2CID   3511305.
  15. ↑ Okutan G, Sánchez Niño GM, Terrén Lora A, López Oliva S, San Mauro Martín I (October 2023). "Exogenous Supplementation with DAO Enzyme in Women with Fibromyalgia: A Double-Blind Placebo-Controlled Clinical Trial". J Clin Med. 12 (20): 6449. doi: 10.3390/jcm12206449 . PMC   10607251 . PMID   37892588.
  16. ↑ Schnedl WJ, Enko D (April 2021). "Histamine Intolerance Originates in the Gut". Nutrients. 13 (4): 1262. doi: 10.3390/nu13041262 . PMC   8069563 . PMID   33921522.
  17. ↑ Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MC (August 2020). "Histamine Intolerance: The Current State of the Art". Biomolecules. 10 (8): 1181. doi: 10.3390/biom10081181 . PMC   7463562 . PMID   32824107.
  18. ↑ Hrubisko M, Danis R, Huorka M, Wawruch M (June 2021). "Histamine Intolerance-The More We Know the Less We Know. A Review". Nutrients. 13 (7): 2228. doi: 10.3390/nu13072228 . PMC   8308327 . PMID   34209583.
  19. ↑ "regulations.gov search for diamine oxidase". Archived from the original on 29 October 2023. Retrieved 29 October 2023.
  20. 1 2 3 4 5 6 Reese I, Ballmer-Weber B, Beyer K, Dölle-Bierke S, Kleine-Tebbe J, Klimek L, et al. (2021). "Guideline on management of suspected adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergology and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA) as well as the Swiss Society for Allergology and Immunology (SGAI) and the Austrian Society for Allergology and Immunology (ÖGAI)". Allergol Select. 5: 305–314. doi:10.5414/ALX02269E. PMC   8511827 . PMID   34651098. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  21. ↑ De Mora F, Messlinger K (2024). "Is calcitonin gene-related peptide (CGRP) the missing link in food histamine-induced migraine? A review of functional gut-to-trigeminovascular system connections". Drug Discovery Today. 29 (4). doi: 10.1016/j.drudis.2024.103941 . PMID   38447930.
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