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MetaCyc Pathway: retinoate biosynthesis II
Traceable author statement to experimental support

Pathway diagram: retinoate biosynthesis II

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: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisVitamin A Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens

Expected Taxonomic Range: Metazoa

General Background

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].

Created 26-Aug-2011 by Caspi R, SRI International


Duester08: Duester G (2008). "Retinoic acid synthesis and signaling during early organogenesis." Cell 134(6);921-31. PMID: 18805086

Holland07: Holland LZ (2007). "Developmental biology: a chordate with a difference." Nature 447(7141);153-5. PMID: 17495912

Napoli11: Napoli JL (2011). "Physiological insights into all-trans-retinoic acid biosynthesis." Biochim Biophys Acta. PMID: 21621639

Taibi01: Taibi G, Paganini A, Gueli MC, Ampola F, Nicotra CM (2001). "Xanthine oxidase catalyzes the synthesis of retinoic acid." J Enzyme Inhib 16(3);275-85. PMID: 11697048

Taibi07: Taibi G, Nicotra CM (2007). "Xanthine oxidase catalyzes the oxidation of retinol." J Enzyme Inhib Med Chem 22(4);471-6. PMID: 17847715

Taibi08: Taibi G, Di Gaudio F, Nicotra CM (2008). "Xanthine dehydrogenase processes retinol to retinoic acid in human mammary epithelial cells." J Enzyme Inhib Med Chem 23(3);317-27. PMID: 18569334

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

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

Blomhoff90: Blomhoff R, Green MH, Berg T, Norum KR (1990). "Transport and storage of vitamin A." Science 250(4979);399-404. PMID: 2218545

Boerman91: Boerman MH, Napoli JL (1991). "Cholate-independent retinyl ester hydrolysis. Stimulation by Apo-cellular retinol-binding protein." J Biol Chem 266(33);22273-8. PMID: 1939249

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

Cowan90: Cowan SW, Newcomer ME, Jones TA (1990). "Crystallographic refinement of human serum retinol binding protein at 2A resolution." Proteins 8(1);44-61. PMID: 2217163

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

Ikegami86: Ikegami T, Nishino T (1986). "The presence of desulfo xanthine dehydrogenase in purified and crude enzyme preparations from rat liver." Arch Biochem Biophys 247(2);254-60. PMID: 3459393

Inagami92: Inagami S, Ong DE (1992). "Purification and partial characterization of cellular retinol-binding protein, type two, from human small intestine." J Nutr 122(3);450-6. PMID: 1542003

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

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

Li91: 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

Li96: Li E, Norris AW (1996). "Structure/function of cytoplasmic vitamin A-binding proteins." Annu Rev Nutr 16;205-34. PMID: 8839926

MacDonald88: MacDonald PN, Ong DE (1988). "A lecithin:retinol acyltransferase activity in human and rat liver." Biochem Biophys Res Commun 156(1);157-63. PMID: 3178828

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Fri Apr 29, 2016, biocyc13.