If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Vitamin A Biosynthesis → Visual Cycles|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
The source of the chromophore in the visual system is all-trans-retinol, derived from the blood circulation (see retinol biosynthesis for its synthesis). The compound is taken up from the choroid blood vessels into the retinal pigment epithelium (RPE) cells, a monolayer of epithelial cells adjacent to the outer segments of photoreceptors. In the RPE all-trans-retinol is converted in several steps to 11-cis-retinal, which is then introduced into the photoreceptors, where it combines with opsin to form the visual pigments.
Following photoactivation of the pigment, the chromophore is released as all-trans-retinal, which is reduced to all-trans-retinol and then removed from the bleached photoreceptors and transported back to the RPE, where it enters the cycle again. Since the supply of new all-trans-retinol from blood vessels is rather slow, the cycle is driven primarily by the recycled photolytic all-trans-retinol released from the bleached photoreceptors.
This process is known as the visual cycle, and it provides 11-cis-retinal for pigment regeneration in both rods and cones.
About This Pathway
When all-trans-retinol arrives in the blood, it is bound as an all-trans-retinol-(plasma-retinol-binding-protein) complex. Upon entering the RPE cells, retinol dissociates from the plasma retinol-binding protein (which remains outside the cells) and binds instead to the cellular retinol-binding protein 1 (RBP1), which diffuses from the apical processes to the RPE cell body. Once there, it is esterified to all-trans retinyl ester by the enzyme lecithin retinol acyltransferase (LRAT). The ester is then hydrolyzed and isomerized into 11-cis-retinol in a single reaction catalyzed by the enzyme retinoid isomerohydrolase (RPE65).
Bound to another protein called cellular retinaldehyde binding protein (RLBP1), 11-cis-retinol is oxidized into 11-cis-retinal by 11-cis retinol dehydrogenase (RDH5). Still bound to RLBP, 11-cis-retinal diffuses to the apical processes of RPE cells, which are close to the photoreceptors outer segments. At the apical processes 11-cis-retinal exits the RPE to the extracellular interphotoreceptor matrix (IPM), possibly facilitated by RLBP and other proteins. Binding with another carrier protein, interphotoreceptor retinoid-binding protein (IRBP), 11-cis-retinal is transferred back to the photoreceptor outer segment, where it recombines with apo-opsin to regenerate the visual pigment.
Photon absorption by 11-cis-retinal converts it to the all-trans form, which is a strong agonist for opsin. The photoisomerization of the retinoid induces a series of rapid conformational changes of the pigment molecule that convert it to the physiologically active state (Meta II) within ~1 milisecond. Meta II is the form of rhodopsin that activates the visual G-protein, transducin, triggering a second messenger cascade. Meta II decays to an inactive form, Meta III, and following the hydrolysis of the Schiff-base bond dissociates into free opsin and all-trans-retinal. This decay takes minutes in rods but only seconds in cones. The released all-trans-retinal is reduced to all-trans-retinol by several NADPH-dependent retinol dehydrogenases, and all-trans-retinol is transferred from the photoreceptors to the apical processes of the RPE cells in a process facilitated by the interphotoreceptor retinoid-binding protein (IRBP). In the RPE, all-trans-retinol binds to the Cellular Retinol Binding Protein and re-enters the cycle.
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
Bentrop86: Bentrop J, Paulsen R (1986). "Light-modulated ADP-ribosylation, protein phosphorylation and protein binding in isolated fly photoreceptor membranes." Eur J Biochem 161(1);61-7. PMID: 3780740
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
Byk93: Byk T, Bar-Yaacov M, Doza YN, Minke B, Selinger Z (1993). "Regulatory arrestin cycle secures the fidelity and maintenance of the fly photoreceptor cell." Proc Natl Acad Sci U S A 90(5);1907-11. PMID: 8446607
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
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
Crabb88: Crabb JW, Goldflam S, Harris SE, Saari JC (1988). "Cloning of the cDNAs encoding the cellular retinaldehyde-binding protein from bovine and human retina and comparison of the protein structures." J Biol Chem 263(35);18688-92. PMID: 3198595
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
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
Eichers02: Eichers ER, Green JS, Stockton DW, Jackman CS, Whelan J, McNamara JA, Johnson GJ, Lupski JR, Katsanis N (2002). "Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1." Am J Hum Genet 70(4);955-64. PMID: 11868161
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
Fong84: Fong SL, Liou GI, Landers RA, Alvarez RA, Bridges CD (1984). "Purification and characterization of a retinol-binding glycoprotein synthesized and secreted by bovine neural retina." J Biol Chem 259(10);6534-42. PMID: 6427217
Showing only 20 references. To show more, press the button "Show all references".
©2014 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493