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., [5]
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., [5]
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+. 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. [6] While ALDH1a3 and related isozymes are known to utilize many aldehyde substrates in biochemical experiments, [7] genetic and functional analysis demonstrates that ALDH1a3 functions only to oxidize all-trans retinaldehyde in living systems. [8] ALDH1a3 exists as a homotetramer [9] with cytosolic localization. It is not known to have any function in healthy adult tissues. [10] ALDH1a3 contains a catalytic cysteine residue which is only minimally inhibited by the ALDH2-targeted drug disulfiram. [7] 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. [11]
The function of ALDH1a3 is known to be restricted to early fetal development and is dispensable in either adult mammals [12] or healthy adult humans. [11] ALDH1a3 is a potential therapeutic target in type 2 diabetes. [13] cardiovascular disorders, [14] [15] and cancer [16] where its expression is amplified and it has known pathogenic activity. [6] ALDH1a3 is not necessary for spermatogenesis [17] or the visual cycle. [6]
ALDH1a3 is established as a primary marker of failing beta cells in the pancreas, both in human type 2 diabetes patients [18] and mouse models of diabetes. [19] ALDH1a3 expression has been shown to suppress insulin secretion and increase glucagon production in laboratory experiments. [20] 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 independence. [13] [21]
ALDH1a3 is activated in injured or inflamed vascular smooth muscle cells in the context of pulmonary arterial hypertension [14] and neointimal hyperplasia. [15] 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. [22]
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, [23] glioblastoma, [24] lung cancer, [25] pancreatic cancer, [26] breast cancer, [27] sarcomas [16] and many other cancer types. [6] 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. [16]
Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most notably β-carotene (beta-carotene). Vitamin A has multiple functions: growth during embryo development, maintaining the immune system, and healthy vision. For aiding vision specifically, it combines with the protein opsin to form rhodopsin, the light-absorbing molecule necessary for both low-light and color vision.
Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and mucous membranes, immune function and reproductive development. Dietary sources include fish, dairy products, and meat. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. It is taken by mouth or by injection into a muscle. As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.
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.
The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. RAR receptors are also known to exhibit many retinoid-independent effects as they bind to and regulate other nuclear receptor pathways, such as the estrogen receptor.
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist. Bexarotene is the only specific activator of the RXRs which does not activate the Retinoic Acid Receptors.
In enzymology, a retinol dehydrogenase (RDH) (EC 1.1.1.105) is an enzyme that catalyzes the chemical reaction
Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.
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:
Retinoid X receptor gamma (RXR-gamma), also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.
Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.
RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.
Free fatty acid receptor 2 (FFAR2), also known as G-protein coupled receptor 43 (GPR43), is a rhodopsin-like G-protein coupled receptor (GPCR) encoded by the FFAR2 gene. In humans, the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12 (19q13.12).
Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial (PDK4) is an enzyme that in humans is encoded by the PDK4 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.
Retinoic acid receptor responder protein 3 is a protein that in humans is encoded by the RARRES3 gene.
Retinol dehydrogenase 12 is an enzyme that in humans is encoded by the RDH12 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.
Retinoic acid receptor responder protein 1 is a protein that in humans is encoded by the RARRES1 gene.
Cytochrome P450 26B1 is a protein that in humans is encoded by the CYP26B1 gene.
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.
Retinol dehydrogenase 13 (all-trans/9-cis) is a protein that in humans is encoded by the RDH13 gene. This gene encodes a mitochondrial short-chain dehydrogenase/reductase, which catalyzes the reduction and oxidation of retinoids. The encoded enzyme may function in retinoic acid production and may also protect the mitochondria against oxidative stress. Alternatively spliced transcript variants have been described.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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