Retinoic acid

Last updated
All-trans-retinoic acid
All-trans-Retinsaure.svg
Retinoic acid 3D ball.png
Names
IUPAC name
Retinoic acid
Systematic IUPAC name
(2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid
Other names
vitamin A acid; RA
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+
    Key: SHGAZHPCJJPHSC-YCNIQYBTSA-N
  • CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C
Properties
C20H28O2
Molar mass 300.43512 g/mol
Appearanceyellow to light orange crystalline powder with a characteristic of a floral scent [1]
Melting point 180 to 182 °C (356 to 360 °F; 453 to 455 K) crystals from ethanol [1]
nearly insoluble
Solubility in fatsoluble
Related compounds
Related compounds
 retinol; retinal; beta-carotene
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A 1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, 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. [2] It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. [3]

Contents

All-trans-retinoic acid (ATRA) is the major occurring retinoic acid, while isomers like 13-cis- and 9-cis-retinoic acid are also present in much lower levels. [4]

The key role of all-trans-retinoic acid in embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin (13-cis-retinoic acid) used for treatment of cancer and acne. Oral megadoses of preformed vitamin A (retinyl palmitate), and all-trans-retinoic acid itself, also have teratogenic potential by this same mechanism.

Mechanism of biological action

All-trans-retinoic acid acts by binding to the retinoic acid receptor (RAR), which is bound to DNA as a heterodimer with the retinoid X receptor (RXR) in regions called retinoic acid response elements (RAREs). Binding of the all-trans-retinoic acid ligand to RAR alters the conformation of the RAR, which affects the binding of other proteins that either induce or repress transcription of a nearby gene (including Hox genes and several other target genes). RARs mediate transcription of different sets of genes controlling differentiation of a variety of cell types, thus the target genes regulated depend upon the target cells. [5] In some cells, one of the target genes is the gene for the retinoic acid receptor itself (RAR-beta in mammals), which amplifies the response. [6] Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid. [2] [3]

The molecular basis for the interaction between all-trans-retinoic acid and the Hox genes has been studied by using deletion analysis in transgenic mice carrying constructs of GFP reporter genes. Such studies have identified functional RAREs within flanking sequences of some of the most 3′ Hox genes (including HOXA1 , HOXB1 , HOXB4 , HOXD4 ), suggesting a direct interaction between the genes and retinoic acid. These types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes. [7]

Biosynthesis

All-trans-retinoic acid can be produced in the body by two sequential oxidation steps that convert all-trans-retinol to retinaldehyde to all-trans-retinoic acid, but once produced it cannot be reduced again to all-trans-retinol. The enzymes that generate retinoic acid for regulation of gene expression include retinol dehydrogenase (Rdh10) that metabolizes retinol to retinaldehyde, and three types of retinaldehyde dehydrogenase, i.e. ALDH1A1 (RALDH1), ALDH1A2 (RALDH2), and ALDH1A3 (RALDH3) [8] that metabolize retinaldehyde to retinoic acid. [2] Enzymes that metabolize excess all-trans-retinol to prevent toxicity include alcohol dehydrogenase and cytochrome P450 (CYP26). [9]

Function in the absence of precursors

All-trans-retinoic acid is responsible for most of the activity of vitamin A1, save visual pigment effects that require retinal (retinaldehyde), and cell metabolism effects that may require retinol itself. Also, some biochemical functions necessary for fertility in vitamin A deficient male and female mammals originally appeared to require all-trans-retinol for rescue, but this is due to a requirement for local conversion of all-trans-retinol to all-trans-retinoic acid, as administered all-trans-retinoic acid does not reach some critical tissues unless given in high amounts. Thus, if animals are fed only all-trans-retinoic acid but no vitamin A1 (all-trans-retinol or retinal), they suffer none of the growth-stunting or epithelial-damaging effects of lack of vitamin A1 (including no xerophthalmia—dryness of the cornea). They do suffer retina degeneration and blindness, due to retinal deficiency.

In addition, vitamin A1-deprived but all-trans-retinoic acid-supplemented male rats exhibit hypogonadism and infertility due to lack of local retinoic acid synthesis in the testis; similar treatment of female rats causes infertility due to fetal resorption caused by a lack of local retinoic acid synthesis in the embryo. [10] [11] The retinoic acid synthesis in testes is catalyzed primarily by the ALDH1A2 (RALDH2) aldehyde dehydrogenase. Suppressing this enzyme has been proposed as a possible way to make a male contraceptive pill, because retinoic acid is necessary for spermatogenesis in humans, much as in rats. [12]

Function in embryonic development

All-trans-retinoic acid (ATRA) is a morphogen signaling molecule, which means it is concentration dependent; malformations can arise when the concentration of ATRA is in excess or deficient. Other molecules that interact with ATRA are FGF8, Cdx and Hox genes, all participating in the development of various structures within the embryo. For example, ATRA plays an important role in activating Hox genes required for hindbrain development. The hindbrain, which later differentiates into the brain stem, serves as a major signaling center defining the border of the head and trunk. [13] A double-sided retinoic acid gradient, that is high in the trunk and low at the junction with the head and tail, represses FGF8 in the developing trunk to allow normal somitogenesis, forelimb bud initiation, and formation of the atria in the heart. [14] During exposure to excess ATRA, the hindbrain becomes enlarged, hindering the growth of other parts of the brain; other developmental abnormalities that can occur during excess ATRA are missing or fused somites, and problems with the aorta and large vessels within the heart. With an accumulation of these malformations, an individual can be diagnosed with DiGeorge syndrome. [15] However, since ATRA partakes in various developmental processes, abnormalities associated with loss of ATRA are not just limited to sites associated with DiGeorge syndrome. Retinoic acid is essential throughout an individual's lifetime, but it is most critical during pregnancy. Without the proper concentrations of ATRA, severe abnormalities can be present and even fatal to the growing fetus. Genetic loss-of-function studies in mouse and zebrafish embryos that eliminate ATRA synthesis or ATRA receptors (RARs) have revealed abnormal development of the somites, forelimb buds, heart, hindbrain, spinal cord, eye, forebrain basal ganglia, kidney, foregut endoderm, etc. [14]

Related Research Articles

<span class="mw-page-title-main">Vitamin A</span> Essential nutrient

Vitamin A is a fat-soluble vitamin and an essential nutrient for animals. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinal, retinoic acid, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: it is essential for embryo development and growth, for maintenance of the immune system, and for vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light and color vision.

<span class="mw-page-title-main">Retinol</span> Chemical compound

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.

<span class="mw-page-title-main">Retinal</span> Chemical compound

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

<span class="mw-page-title-main">Retinoid</span> Group of tetraterpenes, with four terpene units joined head-to-tail

The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth.

<span class="mw-page-title-main">Morphogen</span> Biological substance that guides development by non-uniform distribution

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

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. Due to RAR/RXR heterodimers acting as subtrates to the non steroid hormone ligand retinoid they are extensively involved in cell differentiation, proliferation, and apoptosis.

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 is likely to be the major endogenous mammalian RXR-selective agonist.

The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the photon is absorbed, the 11-cis retinal photoisomerizes into all-trans retinal as it is ejected from the opsin protein. Each molecule of retinal must travel from the photoreceptor cell to the RPE and back in order to be refreshed and combined with another opsin. This closed enzymatic pathway of 11-cis retinal is sometimes called Wald's visual cycle after George Wald (1906–1997), who received the Nobel Prize in 1967 for his work towards its discovery.

In enzymology, a retinol dehydrogenase (RDH) (EC 1.1.1.105) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor alpha (RAR-α), also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">Retinal dehydrogenase</span>

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:

<span class="mw-page-title-main">Retinoid X receptor gamma</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor gamma (RXR-gamma), also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.

<span class="mw-page-title-main">Retinoic acid receptor gamma</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">CRABP2</span> Protein-coding gene in the species Homo sapiens

Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the CRABP2 gene.

<span class="mw-page-title-main">ALDH1A2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">CYP27C1</span> Protein-coding gene in the species Homo sapiens

CYP27C1 is a protein that in humans is encoded by the CYP27C1 gene. The Enzyme Commission number (EC) for this protein is EC 1.14.19.53. The full accepted name is all-trans-retinol 3,4-desaturase and the EC number 1 classifies CYP27C1 as a oxidoreductase that acts on paired donor by reducing oxygen. It is also identifiable by the UniProt code Q4G0S4.

Gut-specific homing is the mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response. This process relies on the key interaction between the integrin α4β7 and the addressin MadCAM-1 on the surfaces of the appropriate cells. Additionally, this interaction is strengthened by the presence of CCR9, a chemokine receptor, which interacts with TECK. Vitamin A-derived retinoic acid regulates the expression of these cell surface proteins.

<span class="mw-page-title-main">RDH13</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Retinol-binding protein</span> Family of proteins that bind retinol

Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.

References

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  3. 1 2 Holland LZ (May 2007). "Developmental biology: a chordate with a difference". Nature. 447 (7141): 153–5. Bibcode:2007Natur.447..153H. doi: 10.1038/447153a . PMID   17495912. S2CID   5549210.
  4. ↑ Rühl R, Krezel W, de Lera AR (December 2018). "9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5". Nutrition Reviews. 76 (12): 929–941. doi: 10.1093/nutrit/nuy057 . PMID   30358857.
  5. ↑ Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, Sarma PV (2013). "In vitro differentiation of cultured human CD34+ cells into astrocytes". Neurology India. 61 (4): 383–8. doi: 10.4103/0028-3886.117615 . PMID   24005729.
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  7. ↑ Marshall H, Morrison A, Studer M, Pöpperl H, Krumlauf R (1996). "Retinoids and Hox genes". The FASEB Journal . 10 (9): 969–978. doi:10.1096/fasebj.10.9.8801179. PMID   8801179. S2CID   16062049.
  8. ↑ "ALDH 1 Family". Dr. Vasilis Vasiliou's laboratory at the University of Colorado's Health Sciences Center. Archived from the original on 13 January 2013. Retrieved 22 October 2012.
  9. ↑ Molotkov A, Ghyselinck NB, Chambon P, Duester G (October 2004). "Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation". The Biochemical Journal. 383 (Pt 2): 295–302. doi:10.1042/BJ20040621. PMC   1134070 . PMID   15193143.
  10. ↑ Moore T, Holmes PD (October 1971). "The production of experimental vitamin A deficiency in rats and mice". Laboratory Animals. 5 (2): 239–50. doi:10.1258/002367771781006492. PMID   5126333. S2CID   34221571.
  11. ↑ van Pelt AM, de Rooij DG (February 1991). "Retinoic acid is able to reinitiate spermatogenesis in vitamin A-deficient rats and high replicate doses support the full development of spermatogenic cells". Endocrinology. 128 (2): 697–704. doi:10.1210/endo-128-2-697. PMID   1989855.
  12. ↑ Kean S (October 2012). "Contraception research. Reinventing the pill: male birth control". Science. 338 (6105): 318–20. Bibcode:2012Sci...338..318K. doi:10.1126/science.338.6105.318. PMID   23087225.
  13. ↑ Lee K, Skromne I (November 2014). "Retinoic acid regulates size, pattern and alignment of tissues at the head-trunk transition". Development. 141 (22): 4375–84. doi: 10.1242/dev.109603 . PMID   25371368.
  14. 1 2 Cunningham TJ, Duester G (February 2015). "Mechanisms of retinoic acid signalling and its roles in organ and limb development". Nature Reviews. Molecular Cell Biology. 16 (2): 110–23. doi:10.1038/nrm3932. PMC   4636111 . PMID   25560970.
  15. ↑ Rhinn M, Dollé P (March 2012). "Retinoic acid signalling during development". Development. 139 (5): 843–58. doi: 10.1242/dev.065938 . PMID   22318625.
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