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Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an
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 ...
that is encoded by the ''ALDH1A1'' gene.


Function

This protein belongs to the
aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...
s family of proteins and is a member of the ALDH1 subfamily (including
ALDH1A2 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. Function ALDH1a2 belongs to the aldehyde dehydrogenase family of prot ...
,
ALDH1A3 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., Function Aldehyde dehydroge ...
, ALDH1B1,
ALDH2 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 majo ...
).
Aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...
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 and thus serve as the only known activator of the rexinoid nuclear receptor pathway. ALDH1A1 has also been described with activity against other substrates in living systems, including all-trans retinaldehyde as well as oxazaphosphorine, a cyclophosphamide metabolite. Unique among the ALDH1 isozymes, ALDH1A1 is known to possess esterase activity in biochemical studies, 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. ALDH1A1 is also expressed in the testes where its function in spermatogenesis is subordinate to and compensatory for ALDH1A2 in mice. ALDH1A1 is inhibited by Antabuse (disulfiram), though the primary pharmacologic target of disulfiram in clinical use is
ALDH2 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 majo ...
. The long clinical history of disulfiram use suggests that ALDH1A1 is not important to normal human physiology. Tumors, specifically in ovarian cancer are found to have a high expression of ALDH1A1.ALDH1A1 is found to cause resistance to chemotherapy.


Clinical significance


Obesity

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 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. This has increased interest in disulfiram as an alternative weight loss therapy to Ozempic, 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. Subsequent efforts to produce ALDH1A1-specific inhibitors have resulted in preclinical compounds that induce weight loss through increased metabolic activity.


Errors due to historical nomenclature

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. Accordingly, ALDH1A1 is often attributed with a role in
alcohol metabolism The pharmacology of ethanol involves both pharmacodynamics (how it affects the body) and pharmacokinetics (how the body processes it). In the body, ethanol primarily affects the central nervous system, acting as a depressant and causing sedatio ...
through oxidation of
acetaldehyde Acetaldehyde (IUPAC systematic name ethanal) is an organic compound, organic chemical compound with the chemical formula, formula , sometimes abbreviated as . It is a colorless liquid or gas, boiling near room temperature. It is one of the most ...
, however,
single nucleotide polymorphisms In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
(SNPs) in this enzyme show little evidence of linkage to
alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...
in humans. Despite established naming conventions, 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.


Species-specific expression

ALDH1A1 possesses unique taxon-specific traits across mammals. Found uniquely in rabbits compared to other mammals, ALDH1A1 appears to function as a
cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
l
crystallin In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast ...
that helps to maintain the transparency of the cornea. In other species such as humans, this role is performed by ALDH3A1. 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.


References


External links

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Further reading

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