| ALDH1A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | ALDH1A1 , ALDC, ALDH-E1, ALDH1, ALDH11, HEL-9, HEL-S-53e, HEL12, PUMB1, RALDH1, aldehyde dehydrogenase 1 family member A1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 100640; MGI: 1353450; HomoloGene: 110441; GeneCards: ALDH1A1; OMA:ALDH1A1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ALDH1A1 gene. [5] [6]
This protein belongs to the aldehyde dehydrogenases family of proteins and is a member of the ALDH1 subfamily (including ALDH1A2, ALDH1A3, ALDH1B1, ALDH2). Aldehyde dehydrogenase isozymes are NAD(P)-dependent dehydrogenases that catalyze the oxidation of an aldehyde into the corresponding carboxylic acid while reducing NAD+ or NADP+. ALDH1A1 is the only ALDH1 isozyme known to oxidize 9-cis retinaldehyde into 9-cis retinoic acid [7] and thus serve as the only known activator of the rexinoid nuclear receptor pathway [8] . ALDH1A1 has also been described with activity against other substrates in living systems, including all-trans retinaldehyde [9] as well as oxazaphosphorine, a cyclophosphamide metabolite [10] . Unique among the ALDH1 isozymes, ALDH1A1 is known to possess esterase activity in biochemical studies [11] , although it is unclear whether this is functionally relevant living tissues.
ALDH1A1 is expressed predominantly in metabolic tissues, including the liver, gastrointestinal tract, thyroid, pituitary gland, and adipose tissues [12] . ALDH1A1 is also expressed in the testes where its function in spermatogenesis is subordinate to and compensatory for ALDH1A2 in mice [9] . ALDH1A1 is inhibited by Antabuse (disulfiram) [13] , though the primary pharmacologic target of disulfiram in clinical use is ALDH2. The long clinical history of disulfiram use suggests that ALDH1A1 is not important to normal human physiology.
The removal of ALDH1A1 in mice through genetic knockout results in viable animals that are fertile and healthy. The only validated phenotype of these mice is a resistance to high fat diet-induced obesity [14] while whole body ALDH1A1 removal does not affect fertility or neurological function. This biology closely replicates the clinical profile of Antabuse (disulfiram). Disulfiram and other ALDH1A1 inhibitors have been shown to cause ALDH1A1-dependent weight loss in obese animals [15] . This has increased interest in disulfiram as an alternative weight loss therapy to Ozempic [16] , yet the rare but potentially fatal liver-damaging effects of disulfiram due to its broad lack of selectivity as well as the alcohol-disulfiram reaction make it unattractive as a weight loss therapy [17] . Subsequent efforts to produce ALDH1A1-specific inhibitors have resulted in preclinical compounds that induce weight loss through increased metabolic activity [18] .
ALDH1A1 is often attributed with multiple biological roles as studies prior to human genome sequencing operated under the assumption that only one ALDH1 gene existed rather than the five isozymes that are annotated today [19] . Accordingly, ALDH1A1 is often attributed with a role in alcohol metabolism through oxidation of acetaldehyde, however, single nucleotide polymorphisms (SNPs) in this enzyme show little evidence of linkage to alcoholism in humans. [20] [21] Despite established naming conventions [19] , many studies still incorrectly use ALDH1 to describe the family of isozymes. For instance, many cancers studies have been interpreted to report on ALDH1A1 activity when the actual protein was ALDH1A3 [22] .
ALDH1A1 possesses unique taxon-specific traits across mammals. Found uniquely in rabbits compared to other mammals, ALDH1A1 appears to function as a corneal crystallin that helps to maintain the transparency of the cornea. In other species such as humans, this role is performed by ALDH3A1 [23] . In beavers, the ALDH1A1 gene has undergone genomic expansion, resulting in approximately 10 copies of the genomic locus, which is putatively linked to a role in lipid balance [24] .
Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. In humans and many other animals, they serve to break down alcohols that are otherwise toxic, and they also participate in the generation of useful aldehyde, ketone, or alcohol groups during the biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.
Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.
Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:
Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, ears, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.
Alcohol tolerance refers to the bodily responses to the functional effects of ethanol. This includes direct tolerance, speed of recovery from insobriety and resistance to the development of alcohol use disorder.
Retinoic acid (simplified nomenclature for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-trans-retinoic acid is required for chordate animal development, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function. and male fertility. Retinoic acid administered as a drug (see tretinoin and alitretinoin) causes significant toxicity that is distinct from normal retinoid biology.
Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.
Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors.
Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.
Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.
In enzymology, a retinal dehydrogenase, also known as retinaldehyde dehydrogenase (RALDH), catalyzes the chemical reaction converting retinal to retinoic acid. This enzyme belongs to the family of oxidoreductases, specifically the class acting on aldehyde or oxo- donor groups with NAD+ or NADP+ as acceptor groups, the systematic name being retinal:NAD+ oxidoreductase. This enzyme participates in retinol metabolism. The general scheme for the reaction catalyzed by this enzyme is:
3-Oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene. It is one of three forms of steroid 5α-reductase.
Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ALDH3A1 gene.
Alcohol dehydrogenase 1A is an enzyme that in humans is encoded by the ADH1A gene.
Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.
4-trimethylaminobutyraldehyde dehydrogenase is an enzyme that in humans is encoded by the ALDH9A1 gene.
Aldehyde dehydrogenase 3 family, member B1 also known as ALDH3B1 is an enzyme that in humans is encoded by the ALDH3B1 gene.
Aldehyde dehydrogenase 1 family, member A3 (ALDH1a3), also known as retinaldehyde dehydrogenase 3 (RALDH3) or as ALDH6 in earlier published studies, is an enzyme that in humans is encoded by the ALDH1A3 gene.,
Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde. This polymorphism is most often reported in patients of East Asian descent. Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. Severe pain after drinking alcohol may indicate a more serious underlying condition.
A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects are caused by accumulation of acetaldehyde, a major but toxic metabolite of alcohol formed by the enzyme alcohol dehydrogenase. The reaction has been variously termed a disulfiram-like reaction, alcohol intolerance, and acetaldehyde syndrome.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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