Aldehyde oxidase (AO) is a metabolizing
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
, located in the cytosolic compartment of tissues in many organisms. AO catalyzes the oxidation of
aldehyde
In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
s into
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
, and in addition, catalyzes the hydroxylation of some
heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...
s.
It can also
catalyze
Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
the oxidation of both
cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
and
monoamine oxidase
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 fi ...
(MAO) intermediate products. AO plays an important role in the
metabolism
Metabolism (, from ''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 cellular processes; the co ...
of several drugs.
Reaction
AO catalyzes the conversion of an aldehyde in the presence of oxygen and water to an acid and
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
.
* an aldehyde + H
2O + O
2 ⇌ a carboxylate + H
2O
2 + H
+
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
and has a very complex
evolutionary profile—as the genes of AO varies according to animal species.
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
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Classification
Immunosuppressive drugs can be classified ...
.
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
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regu ...
pathway. 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
Xanthine oxidase (XO or XAO) 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 ...
(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
A fad, trend, or craze is any form of collective behavior that develops within a culture, a generation, or social group in which a group of people enthusiastically follow an impulse for a short time period.
Fads are objects or behaviors tha ...
,
molybdenum
Molybdenum is a chemical element; it has Symbol (chemistry), symbol Mo (from Neo-Latin ''molybdaenum'') and atomic number 42. The name derived from Ancient Greek ', meaning lead, since its ores were confused with lead ores. Molybdenum minerals hav ...
(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.
Role in drug metabolism
Aldehyde oxidase is thought to have a significant impact on
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
. 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. AO greatly contributes to the hepatic clearance of drugs and other compounds. For example, cytoplasmic AOX1 a key enzyme in the hepatic phase I metabolism of several xenobiotics.
For this reason, AOX genes are becoming increasingly important to both understand and control in the therapeutic drug industry.
Pfizer TLR7 agonist program has found several techniques to switch the AO metabolism off.
Examples of drugs metabolized primarily by aldehyde oxidase are
Zaleplon
Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
,
Ziprasidone
Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The intramuscular form may be used for ...
, and
methotrexate
Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...
.
These drugs are also metabolized by P450 enzymes, and one study could not find any known compounds metabolized purely by AO.
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.
A select few medications have been identified as potentially significant inhibitors of AO, including
Clozapine
Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...
and
Chlorpromazine
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...
.
See also
*
Aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain
References
External links
*
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