Aldehyde dehydrogenase 1 family, member A3 (ALDH1a3), also known as retinaldehyde dehydrogenase 3 (RALDH3) or as ALDH6 in earlier published studies, 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 in humans is encoded by the ''ALDH1A3''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.,
Function
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+. ALDH1a3 oxidizes
all-trans retinaldehyde into
all-trans retinoic acid and thus serves as the final catalytic step in the activation of the
retinoid nuclear receptor (RAR) pathway.
While ALDH1a3 and related isozymes are known to utilize many aldehyde substrates in biochemical experiments,
genetic and functional analysis demonstrates that ALDH1a3 functions only to oxidize all-trans retinaldehyde in living systems.
ALDH1a3 exists as a homotetramer with cytosolic localization. It is not known to have any function in healthy adult tissues. ALDH1a3 contains a catalytic cysteine residue which is only minimally inhibited by the ALDH2-targeted drug
disulfiram
Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by Enzyme inhibition, inhibiting the enzyme aldehyde dehydrogenase (specifically ALD ...
.
While no specific ALDH1a3 inhibitors have been tested in humans, the pan-ALDH1 inhibitor
Win18446 (
Fertilysin) was tested in humans for 23 weeks with no observed adverse effects.
The function of ALDH1a3 is known to be restricted to early fetal development and is dispensable in either adult mammals
or healthy adult humans.
ALDH1a3 is a potential therapeutic target in
type 2 diabetes
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
.
cardiovascular disorders,
and
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
where its expression is amplified and it has known pathogenic activity.
ALDH1a3 is not necessary for spermatogenesis or the visual cycle.
Clinical significance
Type 2 Diabetes
ALDH1a3 is established as a primary marker of failing
beta cell
Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vi ...
s in the pancreas, both in human type 2 diabetes patients and mouse models of diabetes.
ALDH1a3 expression has been shown to suppress insulin secretion and increase glucagon production in laboratory experiments. ALDH1a3 was more recently established as a driver of beta cell failure and thus type 2 diabetes in a retinoid-dependent mechanism. Genetic and pharmacologic experiments with recently described ALDH1a3 inhibitors suggest that ALDH1a3 is a potential target to reverse beta cell decline in type 2 diabetes and thus restore
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
independence.
Cardiovascular Disorders
ALDH1a3 is activated in injured or inflamed vascular smooth muscle cells in the context of pulmonary arterial hypertension
and neointimal hyperplasia.
Activation of ALDH1a3 in these cells causes vascular wall thickening and narrowing of pulmonary arteries, leading to disease progression. Chronic activation of the retinoid nuclear receptor causes increases in mortality due to heart failure.
Cancer
ALDH1a3 is expressed in many cancer types while it is not expressed in the normal cells from which those cancers are derived. There is extensive literature evidence for the selective enrichment of ALDH1a3 across many cancers, including melanoma, glioblastoma, lung cancer, pancreatic cancer, breast cancer,
sarcomas
and many other cancer types.
While the putative role of ALDH1a3 in each of these cancers is via activation of the retinoid pathway, many studies disagree on its mechanism. A unifying theory for its activity in cancer was described through the generation of all-trans retinoic acid that acts in a paracrine manner on immune cells in the tumor microenvironment.
References
Further reading
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External links
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{{Aldehyde dehydrogenases