Retinoic acid

Source: Wikipedia, the free encyclopedia.
For all-trans-retinoic acid as a drug, see Tretinoin. For 9-cis-retinoic acid as a drug, see Alitretinoin. For 13-cis-retinoic acid as a drug, see Isotretinoin.
All-trans-retinoic acid
Skeletal formula of retinoic acid
Ball-and-stick model of the retinoic acid molecule
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
IUPHAR/BPS
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
Appearance yellow 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 fat soluble
Related compounds
Related compounds
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

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]

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

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

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

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

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 pharmaceuticals

References

  1. ^ a b Merck Index, 13th Edition, 8251.
  2. ^
    PMID 18805086
    .
  3. ^
    S2CID 5549210
    .
  4. PMID 30358857
    .
  5. PMID 24005729
    .
  6. ISBN 1-56081-706-2
    .
  7. ^ Marshall H, Morrison A, Studer M, Pöpperl H, Krumlauf R (1996). "Retinoids and Hox genes".
    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. PMID 15193143
    .
  10. S2CID 34221571
    .
  11. PMID 1989855
    .
  12. PMID 23087225
    .
  13. PMID 25371368
    .
  14. ^
    PMID 25560970
    .
  15. PMID 22318625
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Retinoic_acid&oldid=1215636135"