This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: retinoic acid biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Vitamin A Biosynthesis|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
All-trans retinoic acid, one of the forms of vitamin A, is a metabolite of all-trans-retinol that mediates the functions of vitamin A required for growth and development, and is required in all chordate animals. During early embryonic development, 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 [Duester08]. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages [Holland07].
In the adult, the normal growth and differentiation of the epidermis require an adequate supply of all-trans-retinoate, which is responsible for most of the activity of vitamin A, save visual pigment effects which require all-trans-retinal (see pathway the visual cycle I (vertebrates)), and some cell metabolism effects that may require all-trans-retinol. Retinoic acid controls the expression of retinoid-responsive genes via interactions of the retinoic acid/nuclear receptor complexes at specific DNA sequences in their control regions.
About This Pathway
The cytosolic enzyme xanthine oxidase (which also exists in a second form known as xanthine dehydrogenase) generates all-trans-retinoate from all-trans-retinol in human mammary epithelial cells. The substrate must be bound to a cellular-retinol-binding protein.
Both forms of the protein can form retinoate, although via different mechanisms. The xanthine dehydrogenase form can generate all-trans-retinoate directly, as shown here [Taibi08]. The xanthine oxidase form catalyzes two reactions - the oxidation of an all-trans retinol-[cellular-retinol-binding-protein] to an all-trans retinal-[cellular-retinol-binding-protein], followed by oxidation of the latter to all-trans-retinoate [Taibi01, Taibi07].
This biological significance of this observation is not completely understood, but it may represent a cytosolic pathway for production of all-trans-retinoate. It has been reported that 6 to 20% of cellular retinal-generating capacity occurs in the cytosol [Napoli11].
Biesalski99: Biesalski HK, Frank J, Beck SC, Heinrich F, Illek B, Reifen R, Gollnick H, Seeliger MW, Wissinger B, Zrenner E (1999). "Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol binding protein." Am J Clin Nutr 69(5);931-6. PMID: 10232633
Colantuoni83: Colantuoni V, Romano V, Bensi G, Santoro C, Costanzo F, Raugei G, Cortese R (1983). "Cloning and sequencing of a full length cDNA coding for human retinol-binding protein." Nucleic Acids Res 11(22);7769-76. PMID: 6316270
Colantuoni85: Colantuoni V, Cortese R, Nilsson M, Lundvall J, Bavik CO, Eriksson U, Peterson PA, Sundelin J (1985). "Cloning and sequencing of a full length cDNA corresponding to human cellular retinol-binding protein." Biochem Biophys Res Commun 130(1);431-9. PMID: 2992469
Cowan93: Cowan SW, Newcomer ME, Jones TA (1993). "Crystallographic studies on a family of cellular lipophilic transport proteins. Refinement of P2 myelin protein and the structure determination and refinement of cellular retinol-binding protein in complex with all-trans-retinol." J Mol Biol 230(4);1225-46. PMID: 7683727
De98: De Baere E, Speleman F, Van Roy N, De Paepe A, Messiaen L (1998). "Assignment of the cellular retinol-binding protein 1 gene (RBP1) and of the coatomer beta subunit gene (COPB2) to human chromosome band 3q23 by in situ hybridization." Cytogenet Cell Genet 82(3-4);226-7. PMID: 9858824
DOnofrio85: D'Onofrio C, Colantuoni V, Cortese R (1985). "Structure and cell-specific expression of a cloned human retinol binding protein gene: the 5'-flanking region contains hepatoma specific transcriptional signals." EMBO J 4(8);1981-9. PMID: 2998779
Gok03: Gok F, Ichida K, Topaloglu R (2003). "Mutational analysis of the xanthine dehydrogenase gene in a Turkish family with autosomal recessive classical xanthinuria." Nephrol Dial Transplant 18(11);2278-83. PMID: 14551354
Ichida93: Ichida K, Amaya Y, Noda K, Minoshima S, Hosoya T, Sakai O, Shimizu N, Nishino T (1993). "Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene." Gene 133(2);279-84. PMID: 8224915
Ichida97: Ichida K, Amaya Y, Kamatani N, Nishino T, Hosoya T, Sakai O (1997). "Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria." J Clin Invest 99(10);2391-7. PMID: 9153281
Isken08: Isken A, Golczak M, Oberhauser V, Hunzelmann S, Driever W, Imanishi Y, Palczewski K, von Lintig J (2008). "RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome." Cell Metab 7(3);258-68. PMID: 18316031
Levartovsky00: Levartovsky D, Lagziel A, Sperling O, Liberman U, Yaron M, Hosoya T, Ichida K, Peretz H (2000). "XDH gene mutation is the underlying cause of classical xanthinuria: a second report." Kidney Int 57(6);2215-20. PMID: 10844591
Li91a: Li E, Qian SJ, Winter NS, d'Avignon A, Levin MS, Gordon JI (1991). "Fluorine nuclear magnetic resonance analysis of the ligand binding properties of two homologous rat cellular retinol-binding proteins expressed in Escherichia coli." J Biol Chem 266(6);3622-9. PMID: 1995621
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