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MetaCyc Pathway: retinol biosynthesis
Inferred by curator

Pathway diagram: retinol biosynthesis

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: vitamin A biosynthesis, retinal biosynthesis, retinoid 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

Vitamin A is the name given to a family of related compounds from the retinoid group, including all-trans forms such as all-trans-retinol, all-trans-retinal and all-trans-retinoate, cis forms such as 11-cis-retinol, 11-cis-retinal, 9-cis-retinoate and 13-cis-retinoate, and retinyl esters such as all-trans-retinyl palmitate. Structurally, all retinoids possess a β-ionone ring and a polyunsaturated side chain, with either an alcohol, aldehyde, a carboxylic acid group or an ester group. The side chain is composed of two isoprenoid units, with a series of conjugated double bonds which may exist in trans- or cis-configuration.

Vitamin A compounds have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes.

Animals can not synthesize vitamin A de novo and require a dietary supplement. Carnivorous vertebrate animals can obtain it directly from dietary meat, in the form of retinyl-esters. Vegetarian animals produce retinal from one of four carotenoids: all-trans-β-carotene, β-cryptoxanthin, α-carotene, and γ-carotene, which they must obtain from plants or other photosynthetic organisms [Kim09d].

11-cis-retinal is a polyene chromophore, and when bound to opsin proteins it forms the chemical basis of animal vision (see pathway the visual cycle I (vertebrates)). Some microorganisms utilize a similar system in which various cis forms of retinal bound to proteins called type 1 rhodopsins allow them to convert light into metabolic energy.

All-trans retinoate is the vitamin A form that mediates the functions required for growth and development. During early embryonic development, retinoate 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, retinoate is responsible for most of the activity of vitamin A (see retinoate biosynthesis I).

Retinoid-Binding Proteins

Due to the insolubility of retinoids, they are bound within the cell (or plasma) to specialized binding proteins. The sequestration of retinoids inside high-affinity binding-proteins increases their solubility, protects them from unfettered metabolism, and facilitates their transportation within the body, while still allowing access to the enzymes that metabolize them (e.g. the formation of retinyl esters) [Cowan93, Newcomer98]. Several retinoid-binding proteins exist. The cellular-retinol binding proteins (encoded by RBP1 and RBP2) bind free retinol within the cell, and continue to bind it even after it has been oxidized to retinal. RBP2 is expressed only in the small intestine, where it is involved in binding the retinol freshly obtained from dietary input. RBP1 is the main retinoid-binding protein in other cells, and also serves an a sensor for retinol availability, modulating activity of several retinol-metabolizing enzymes. The interphotoreceptor retinoid-binding protein, encoded by RBP3, shuttles retinoids between the pigment epithelium and the visual pigments in the photoreceptor cells of the retina. The plasma retinol-binding protein ( RBP4) delivers retinol form liver storage to the peripheral tissues. The retinaldehyde-binding protein 1 ( RLBP1) binds different forms of retinal and is essential for the proper function of both rod and cone photoreceptors.

Initial Synthesis of all-trans-retinol

There are two dietary inputs of retinoids. Ingested retinyl-esters are broken in the intestine into all-trans-retinol, which is immediately bound to a cellular-retinol-binding protein. Ingested carotenoids are processed by β,β-carotene 15,15'-dioxygenase into all-trans-retinal, which is reduced to all-trans-retinol by several dehydrogenases and processed in the same way.


After binding to a cellular-retinol-binding protein, all-trans-retinol is esterified by lecithin retinol acyltransferase ( LRAT) with long chain fatty acids, primarily palmitate, to form retinyl esters that are incorporated into the hydrophobic core of chylomicrons (large lipoprotein particles that transport dietary lipids from the intestines to other locations in the body). The chylomicrons are secreted into the lymph and ultimately enter the blood via the thoracic and other lymphatic ducts. Chylomicron remnants are taken up by the liver and the retinyl esters are stored. When needed, these esters are hydrolyzed to regenerate the retinol.


When the concentration of retinoids falls, the retinyl esters in the liver are hydrolyzed by neutral and acid retinyl ester hydrolases, such as liver carboxylesterase 1 monomer ( CES1), releasing all-trans-retinol [Linke05]. The retinol is transferred to the endoplasmic reticulum (ER), where it binds to plasma retinol-binding protein ( RBP4) and is secreted into the circulation as an all-trans-retinol-(plasma-retinol-binding-protein) complex.


All-trans-retinol is utilized mostly for production of 11-cis-retinal and all-trans-retinoate. These processes are described in the visual cycle I (vertebrates) and retinoate biosynthesis I pathways.

Created 09-Aug-2011 by Caspi R, SRI International


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

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

Kim09d: Kim YS, Oh DK (2009). "Substrate specificity of a recombinant chicken beta-carotene 15,15'-monooxygenase that converts beta-carotene into retinal." Biotechnol Lett 31(3);403-8. PMID: 18979213

Linke05: Linke T, Dawson H, Harrison EH (2005). "Isolation and characterization of a microsomal acid retinyl ester hydrolase." J Biol Chem 280(24);23287-94. PMID: 15767260

Newcomer98: Newcomer ME, Jamison RS, Ong DE (1998). "Structure and function of retinoid-binding proteins." Subcell Biochem 30;53-80. PMID: 9932510

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

Aldahmesh09: Aldahmesh MA, Safieh LA, Alkuraya H, Al-Rajhi A, Shamseldin H, Hashem M, Alzahrani F, Khan AO, Alqahtani F, Rahbeeni Z, Alowain M, Khalak H, Al-Hazzaa S, Meyer BF, Alkuraya FS (2009). "Molecular characterization of retinitis pigmentosa in Saudi Arabia." Mol Vis 15;2464-9. PMID: 19956407

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

Blaner87: Blaner WS, Das SR, Gouras P, Flood MT (1987). "Hydrolysis of 11-cis- and all-trans-retinyl palmitate by homogenates of human retinal epithelial cells." J Biol Chem 262(1);53-8. PMID: 3793734

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

Brzezinski94: Brzezinski MR, Abraham TL, Stone CL, Dean RA, Bosron WF (1994). "Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine." Biochem Pharmacol 48(9);1747-55. PMID: 7980644

Chetyrkin01: Chetyrkin SV, Belyaeva OV, Gough WH, Kedishvili NY (2001). "Characterization of a novel type of human microsomal 3alpha -hydroxysteroid dehydrogenase: unique tissue distribution and catalytic properties." J Biol Chem 276(25);22278-86. PMID: 11294878

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

De98: De Baere E, Speleman F, Van Roy N, Mortier K, De Paepe A, Messiaen L (1998). "Assignment of the cellular retinol-binding protein 2 gene (RBP2) to human chromosome band 3q23 by in situ hybridization." Cytogenet Cell Genet 83(3-4);240-1. PMID: 10072590

De98a: 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

delaSena14: dela Sena C, Riedl KM, Narayanasamy S, Curley RW, Schwartz SJ, Harrison EH (2014). "The human enzyme that converts dietary provitamin A carotenoids to vitamin A is a dioxygenase." J Biol Chem 289(19);13661-6. PMID: 24668807

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

Farjo09: Farjo KM, Moiseyev G, Takahashi Y, Crouch RK, Ma JX (2009). "The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins." Invest Ophthalmol Vis Sci 50(11);5089-97. PMID: 19458327

Farjo11: Farjo KM, Moiseyev G, Nikolaeva O, Sandell LL, Trainor PA, Ma JX (2011). "RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism and retinoic acid synthesis." Dev Biol. PMID: 21782811

Fierce08: Fierce Y, de Morais Vieira M, Piantedosi R, Wyss A, Blaner WS, Paik J (2008). "In vitro and in vivo characterization of retinoid synthesis from beta-carotene." Arch Biochem Biophys 472(2);126-38. PMID: 18295589

Ghosh00: Ghosh S (2000). "Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of full-length cDNA." Physiol Genomics 2(1);1-8. PMID: 11015575

Haeseleer02: Haeseleer F, Jang GF, Imanishi Y, Driessen CA, Matsumura M, Nelson PS, Palczewski K (2002). "Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina." J Biol Chem 277(47);45537-46. PMID: 12226107

Haeseleer98: Haeseleer F, Huang J, Lebioda L, Saari JC, Palczewski K (1998). "Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal." J Biol Chem 273(34);21790-9. PMID: 9705317

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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
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