Aldehyde oxidase

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Aldehyde oxidase
Aldehydoxidase.png
Model of human aldehyde oxidase after PDB: 4UHW .
Identifiers
EC no. 1.2.3.1
CAS no. 9029-07-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
aldehyde oxidase 1
Identifiers
Symbol AOX1
NCBI gene 316
HGNC 553
OMIM 602841
RefSeq NM_001159
UniProt Q06278
Other data
EC number 1.2.3.1
Locus Chr. 2 q33
Search for
Structures Swiss-model
Domains InterPro

Aldehyde oxidase (AO) is a metabolizing enzyme, located in the cytosolic compartment of tissues in many organisms. AO catalyzes the oxidation of aldehydes into carboxylic acid, and in addition, catalyzes the hydroxylation of some heterocycles. [1] It can also catalyze the oxidation of both cytochrome P450 and monoamine oxidase (MAO) intermediate products. AO plays an important role in the metabolism of several drugs.

Contents

Reaction

AO catalyzes the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide.

Though the enzyme uses molecular oxygen as an electron acceptor, the oxygen atom that is incorporated into the carboxylate product is from water; however, the exact mechanism of reduction is still not known for AO.

The AO also catalyzes the oxidation of heterocycles, which involves a nucleophilic attack located at the carbon atom beside the heteroatom. This means that susceptibility to nucleophilic attack of a heterocycle determines if that heterocycle is a suitable substrate for AO.

Species distribution

Aldehyde oxidase is a member of the molybdenum flavoprotein family [1] and has a very complex evolutionary profile—as the genes of AO varies according to animal species. [2] Higher primates, such as humans, have a single functioning AO gene (AOX1), whereas rodents have four separate AOX genes. The human population has both functionally inactive hAOX1 allelic variants and encoding enzyme variants with different catalytic activities. AO activity has been found to be much more active in higher primates (compared to rodents), though many factors may affect this activity, such as gender, age, cigarette smoking, drug usage, and disease states.

Tissue distribution

Aldehyde oxidase is very concentrated in the liver, where it oxidizes multiple aldehydes and nitrogenous heterocyclic compounds, such as anti-cancer and immunosuppressive drugs. [1] Some AO activity has been located in other parts of the body—including the lungs (epithelial cells and alveolar cells), the kidneys, and the gastrointestinal tract (small and large intestines).

Regulation

The regulation of expression of AO is still not completely known, though some studies have shown that the AOX1 gene is regulated by the Nrf2 pathway. [3] Some known inhibitors of AO are sterol and phenol compounds, like estradiol. Others include amsacrine, 6,6'-azopurine, chlorpromazine, cimetidine, cyanide, diethylstilbestrol, genestein, isovanillin, and methadone.

Structure

AO is very similar in amino acid sequence to xanthine oxidase (XO). The active sites of AO has been found to have a superimposed structure to that of XO, in studies involving mouse liver. AO is a homodimer, and requires FAD, molybdenum (MoCo) and two 2Fe-2S clusters as cofactors. These two 2Fe-2S cofactors each bind to the two distinct 150-kDa monomers of AO. Three separate domains harbor these three requirements. There is a 20 kDa N-terminal which binds to the two 2Fe-2S cofactors, a 40 kDa domain which provides a means of binding to the FAD, and a C-terminal which houses the molybdenum. [4]

Role in drug metabolism

Aldehyde oxidase is thought to have a significant impact on pharmacokinetics. AO is capable of oxidizing many drugs in the liver (such as N-1-methylnicotinamide, N-methylphthalazinium, benzaldehyde, retinal, and vanillin), because of its broad substrate specificity. [5] AO greatly contributes to the hepatic clearance of drugs and other compounds. [6] For example, cytoplasmic AOX1 a key enzyme in the hepatic phase I metabolism of several xenobiotics. [2] For this reason, AOX genes are becoming increasingly important to both understand and control in the therapeutic drug industry. [2] Pfizer TLR7 agonist program has found several techniques to switch the AO metabolism off. [7] Examples of drugs metabolized primarily by aldehyde oxidase are Zaleplon, Ziprasidone, and methotrexate. [8] These drugs are also metabolized by P450 enzymes, and one study could not find any known compounds metabolized purely by AO. [8] The birth control drug Ethinyl estradiol inhibits AO, but its typical concentration is so low that the potential for drug-drug interaction is essentially zero. [8] A select few medications have been identified as potentially significant inhibitors of AO, including Clozapine and Chlorpromazine. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Xanthine oxidase</span> Class of enzymes

Xanthine oxidase is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzymatic metabolism in the organisms, as well as by abiotic chemical reactions. While the parent drug are usually less active, both the parent drug and its metabolite can be chemically active and cause toxicity, leading to mutagenesis, teratogenesis, and carcinogenesis. Different classes of enzymes, such as P450-monooxygenases, epoxide hydrolase, or acetyltransferases can catalyze the process in the cell, mostly in the liver.

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

Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase.

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

Isovanillin is a phenolic aldehyde, an organic compound and isomer of vanillin. It is a selective inhibitor of aldehyde oxidase. It is not a substrate of that enzyme, and is metabolized by aldehyde dehydrogenase into isovanillic acid, which could make it a candidate drug for use in alcohol aversion therapy. Isovanillin can be used as a precursor in the chemical total synthesis of morphine. The proposed metabolism of isovanillin in rat has been described in literature, and is part of the WikiPathways machine readable pathway collection.

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

Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. Synonyms for molybdopterin are: MPT and pyranopterin-dithiolate. The nomenclature for this biomolecule can be confusing: Molybdopterin itself contains no molybdenum; rather, this is the name of the ligand that will bind the active metal. After molybdopterin is eventually complexed with molybdenum, the complete ligand is usually called molybdenum cofactor.

<span class="mw-page-title-main">Sulfite oxidase</span>

Sulfite oxidase is an enzyme in the mitochondria of all eukaryotes, with exception of the yeasts. It oxidizes sulfite to sulfate and, via cytochrome c, transfers the electrons produced to the electron transport chain, allowing generation of ATP in oxidative phosphorylation. This is the last step in the metabolism of sulfur-containing compounds and the sulfate is excreted.

<span class="mw-page-title-main">CYP2B6</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

In enzymology, an aldehyde dehydrogenase (FAD-independent) (EC 1.2.99.7) is an enzyme that catalyzes the chemical reaction

Arsenate reductase (azurin) (EC 1.20.9.1) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Flavin containing monooxygenase 1</span> Protein-coding gene in the species Homo sapiens

Dimethylaniline monooxygenase [N-oxide-forming] 1 is an enzyme that in humans is encoded by the FMO1 gene.

<span class="mw-page-title-main">CYP4F2</span> Enzyme protein in the species Homo sapiens

Cytochrome P450 4F2 is a protein that in humans is encoded by the CYP4F2 gene. This protein is an enzyme, a type of protein that catalyzes chemical reactions inside cells. This specific enzyme is part of the superfamily of cytochrome P450 (CYP) enzymes, and the encoding gene is part of a cluster of cytochrome P450 genes located on chromosome 19.

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

Molybdenum cofactor sulfurase is an enzyme that in humans is encoded by the MOCOS gene.

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

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

<span class="mw-page-title-main">Aldehyde oxidase 1</span> Protein-coding gene in the species Homo sapiens

Aldehyde oxidase 1 is an enzyme that in humans is encoded by the AOX1 gene.

The aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain is an evolutionary conserved protein domain.

<span class="mw-page-title-main">Molybdenum in biology</span> Use of Molybdenum by organisms

Molybdenum is an essential element in most organisms. It is most notably present in nitrogenase which is an essential part of nitrogen fixation.

References

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  2. 1 2 3 Garattini E, Terao M (Apr 2012). "The role of aldehyde oxidase in drug metabolism". Expert Opinion on Drug Metabolism & Toxicology. 8 (4): 487–503. doi:10.1517/17425255.2012.663352. PMID   22335465. S2CID   24862503.
  3. Maeda K, Ohno T, Igarashi S, Yoshimura T, Yamashiro K, Sakai M (Sep 2012). "Aldehyde oxidase 1 gene is regulated by Nrf2 pathway". Gene. 505 (2): 374–8. doi:10.1016/j.gene.2012.06.010. hdl: 2115/50082 . PMID   22705828.
  4. Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD (Dec 2010). "Aldehyde oxidase: an enzyme of emerging importance in drug discovery". Journal of Medicinal Chemistry. 53 (24): 8441–60. doi:10.1021/jm100888d. PMID   20853847.
  5. Strelevitz TJ, Orozco CC, Obach RS (Jul 2012). "Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance". Drug Metabolism and Disposition. 40 (7): 1441–8. doi:10.1124/dmd.112.045195. PMID   22522748. S2CID   16505283.
  6. Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro JF, Jones JP, Leimkühler S (May 2012). "The impact of single nucleotide polymorphisms on human aldehyde oxidase". Drug Metabolism and Disposition. 40 (5): 856–64. doi:10.1124/dmd.111.043828. PMC   4738704 . PMID   22279051.
  7. Pryde DC, Tran TD, Jones P, Duckworth J, Howard M, Gardner I, Hyland R, Webster R, Wenham T, Bagal S, Omoto K, Schneider RP, Lin J (Apr 2012). "Medicinal chemistry approaches to avoid aldehyde oxidase metabolism". Bioorganic & Medicinal Chemistry Letters. 22 (8): 2856–60. doi:10.1016/j.bmcl.2012.02.069. PMID   22429467.
  8. 1 2 3 4 Barr JT, Jones JP (December 2011). "Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions". Drug Metabolism and Disposition. 39 (12): 2381–2386. doi:10.1124/dmd.111.041806. PMC   3226377 . PMID   21940905.