Editing Retinal

{{short description|Vitamin A aldehyde, a polyene chromophore}}
{{Distinguish|Retinol}}
{{About|the molecule|the anatomical feature|Retina}}
{{Chembox
| Watchedfields = changed
| verifiedrevid = 444085949
| Name = All-trans-retinal
| ImageFile = All-trans-Retinal.svg
| ImageSize = 250
| ImageAlt = Skeletal formula of retinal
| ImageFile1 = Retinal 3D ball.png
| ImageSize1 = 260
| ImageAlt1 = Ball-and-stick model of the retinal molecule
| IUPACName = Retinal
| SystematicName = (2''E'',4''E'',6''E'',8''E'')-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenal
| OtherNames = {{Bulleted list|Retinene|Retinaldehyde|Vitamin A aldehyde|RAL}}
|Section1={{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 116-31-4
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = RR725D715M
|  PubChem = 638015
|  ChemSpiderID = 553582
|  ChEBI = 17898
|  StdInChI = 1S/C20H28O/c1-16(8-6-9-17(2)13-15-21)11-12-19-18(3)10-7-14-20(19,4)5/h6,8-9,11-13,15H,7,10,14H2,1-5H3/b9-6+,12-11+,16-8+,17-13+
|  StdInChIKey = NCYCYZXNIZJOKI-OVSJKPMPSA-N
| SMILES = CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C=O)/C)/C}}
|Section2={{Chembox Properties
| C=20 | H=28 | O=1
| Appearance = Orange crystals from [[petroleum ether]]<ref name="Merck">''Merck Index'', 13th Edition, '''8249'''</ref>
| Density =
| MeltingPtC = 61 to 64
| MeltingPt_ref = <ref name="Merck"/>
| BoilingPt = 
| Solubility = Nearly insoluble
| SolubleOther = Soluble
| Solvent = fat}}
|Section7={{Chembox Hazards
| MainHazards = 
| FlashPt = 
| AutoignitionPt = }}
|Section8={{Chembox Related
| OtherFunction = 
| OtherFunction_label = 
| OtherCompounds = [[retinol]]; [[retinoic acid]]; [[beta-carotene]]; [[dehydroretinal]]; 3-hydroxyretinal; 4-hydroxyretinal}}
}}

'''Retinal''' (also known as '''retinaldehyde''') is a [[polyene]] [[chromophore]]. Retinal, bound to proteins called [[opsin]]s, is the chemical basis of [[visual phototransduction]], the light-detection stage of [[visual perception]] (vision).

Some microorganisms use retinal to convert light into metabolic energy. One study suggests that approximately three billion years ago, most living organisms on Earth used retinal, rather than [[chlorophyll]], to convert sunlight into energy. Because retinal absorbs mostly green light and transmits purple light, this gave rise to the [[Purple Earth hypothesis]].<ref>{{Cite journal |last1=DasSarma |first1=Shiladitya |last2=Schwieterman |first2=Edward W. |date=2018 |title=Early evolution of purple retinal pigments on Earth and implications for exoplanet biosignatures |journal=International Journal of Astrobiology |language=en |publication-date=2018-10-11 |volume=20 |issue=3 |pages=241–250 |doi=10.1017/S1473550418000423 |s2cid=119341330 |issn=1473-5504|doi-access=free |arxiv=1810.05150 }}</ref>

Retinal itself is considered to be a form of [[vitamin A]] when eaten by an animal. There are many forms of vitamin A, all of which are converted to retinal, which cannot be made without them. The number of different molecules that can be converted to retinal varies from species to species. Retinal was originally called '''[[retinene]]''',<ref name=Wald1934>{{cite journal |last1=Wald |first1=George |title=Carotenoids and the Vitamin A Cycle in Vision |journal=Nature |date=14 July 1934 |volume=134 |issue=3376 |pages=65 |doi=10.1038/134065a0 |bibcode=1934Natur.134...65W |s2cid=4022911|doi-access=free }}</ref> and was renamed<ref name=Wald1968>{{cite journal |last1=Wald |first1=G. |title=Molecular basis of visual excitation |journal=Science |date=11 October 1968 |volume=162 |issue=3850 |pages=230–9 |pmid=4877437 |doi=10.1126/science.162.3850.230 |bibcode=1968Sci...162..230W}}</ref> after it was discovered to be '''vitamin A [[aldehyde]]'''.<ref name=Morton1944>{{cite journal |last1=MORTON |first1=R. A. |last2=GOODWIN |first2=T. W. |title=Preparation of Retinene in Vitro |journal=Nature |date=1 April 1944 |volume=153 |issue=3883 |pages=405–406 |doi=10.1038/153405a0 |bibcode=1944Natur.153..405M |s2cid=4111460}}</ref><ref name=Ball1946>{{cite journal |last1=Ball |first1=S. |last2=Goodwin |first2=T. W. |last3=Morton |first3=R. A. |title=Retinene1-vitamin A aldehyde. |journal=The Biochemical Journal |date=1946 |volume=40 |issue=5–6 |pages=lix |pmid=20341217}}</ref>

[[Vertebrate]] animals ingest retinal directly from meat, or they produce retinal from [[carotenoid]]s – either from [[alpha-Carotene|α-carotene]] or [[β-Carotene|β-carotene]] – both of which are [[carotene]]s. They also produce it from [[beta-Cryptoxanthin|β-cryptoxanthin]], a type of [[xanthophyll]]. These carotenoids must be obtained from plants or other [[photosynthetic]] organisms. No other carotenoids can be converted by animals to retinal. Some carnivores cannot convert any carotenoids at all. The other main forms of vitamin A – [[retinol]] and a partially active form, [[retinoic acid]] – may both be produced from retinal.

[[Invertebrate]]s such as [[insect]]s and [[squid]] use hydroxylated forms of retinal in their visual systems, which derive from conversion from other [[xanthophylls]].

==Vitamin A metabolism==

Living organisms produce retinal by irreversible oxidative cleavage of carotenoids.<ref name="von Lintig">{{cite journal |last1=von Lintig |first1=Johannes |last2=Vogt |first2=Klaus |year=2000 |title=Filling the Gap in Vitamin A Research: Molecular Identification of An Enzyme Cleaving Beta-carotene to Retinal |journal=Journal of Biological Chemistry |volume=275 |issue=16 |pages=11915–11920 |pmid=10766819 |doi=10.1074/jbc.275.16.11915 |doi-access=free}}</ref>

For example:
{{block indent|[[beta-carotene]] + O<sub>2</sub> → 2 retinal,}}

catalyzed by a [[beta-carotene 15,15'-monooxygenase]]<ref>{{cite journal |last=Woggon |first=Wolf-D. |year=2002 |title=Oxidative cleavage of carotenoids catalyzed by enzyme models and beta-carotene 15,15'-monooxygenase |journal=Pure and Applied Chemistry |volume=74 |issue=8 |pages=1397–1408 |doi=10.1351/pac200274081397 |doi-access=free}}</ref> or a beta-carotene 15,15'-dioxygenase.<ref name="Kim09">{{cite journal |last1=Kim |first1=Yeong-Su |last2=Kim |first2=Nam-Hee |last3=Yeom |first3=Soo-Jin |last4=Kim |first4=Seon-Won |last5=Oh |first5=Deok-Kun |year=2009 |title=In Vitro Characterization of a Recombinant Blh Protein from an Uncultured Marine Bacterium as a β-Carotene 15,15′-Dioxygenase |journal=Journal of Biological Chemistry |volume=284 |issue=23 |pages=15781–93 |pmid=19366683 |doi=10.1074/jbc.M109.002618 |pmc=2708875|doi-access=free }}</ref>

Just as carotenoids are the precursors of retinal, retinal is the precursor of the other forms of vitamin A.  Retinal is interconvertible with [[retinol]], the transport and storage form of vitamin A:
{{block indent|retinal + [[nicotinamide adenine dinucleotide phosphate|NADPH]] + H<sup>+</sup> {{eqm}} retinol + NADP<sup>+</sup>}}
{{block indent|retinol + [[nicotinamide adenine dinucleotide|NAD]]<sup>+</sup> {{eqm}} retinal + NADH + H<sup>+</sup>,}}

catalyzed by [[retinol dehydrogenase]]s (RDHs)<ref>{{cite journal |last1=Lidén |first1=M |last2=Eriksson |first2=U |year=2006 |title=Understanding Retinol Metabolism: Structure and Function of Retinol Dehydrogenases |journal=Journal of Biological Chemistry |volume=281 |issue=19 |pages=13001–04 |doi=10.1074/jbc.R500027200 |pmid=16428379 |doi-access=free}}</ref> and [[alcohol dehydrogenase]]s (ADHs).<ref name="Duester">{{cite journal |last1=Duester |first1=G |title=Retinoic Acid Synthesis and Signaling during Early Organogenesis |journal=Cell |volume=134 |issue=6 |pages=921–31 |date=September 2008 |pmid=18805086 |pmc=2632951 |doi=10.1016/j.cell.2008.09.002}}</ref>

Retinol is called vitamin A [[Alcohol (chemistry)|alcohol]] or, more often, simply vitamin A. Retinal can also be oxidized to [[retinoic acid]]:
{{block indent|retinal + NAD<sup>+</sup> + H<sub>2</sub>O → retinoic acid + NADH + H<sup>+</sup> (catalyzed by RALDH)}}
{{block indent|retinal + O<sub>2</sub> + H<sub>2</sub>O → retinoic acid + H<sub>2</sub>O<sub>2</sub> (catalyzed by retinal oxidase),}}

catalyzed by [[retinal dehydrogenase]]s<ref>{{cite journal |last1=Lin |first1=Min |last2=Zhang |first2=Min |last3=Abraham |first3=Michael |last4=Smith |first4=Susan M. |last5=Napoli |first5=Joseph L. |year=2003 |title=Mouse Retinal Dehydrogenase 4 (RALDH4), Molecular Cloning, Cellular Expression, and Activity in 9-cis-Retinoic Acid Biosynthesis in Intact Cells |journal=Journal of Biological Chemistry |volume=278 |issue=11 |pages=9856–9861 |doi=10.1074/jbc.M211417200 |pmid=12519776 |doi-access=free}}</ref> also known as retinaldehyde dehydrogenases (RALDHs)<ref name="Duester"/> as well as [[retinal oxidase]]s.<ref>{{cite web |url=https://www.genome.jp/dbget-bin/www_bget?enzyme+1.2.3.11 |title=KEGG ENZYME: 1.2.3.11 retinal oxidase |access-date=2009-03-10}}</ref>

Retinoic acid, sometimes called vitamin A [[carboxylic acid|acid]], is an important signaling molecule and hormone in vertebrate animals.

==Vision==
Retinal is a [[conjugated system#Chromophores|conjugated chromophore]]. In the [[Vertebrate eyes]], retinal begins in an 11-''cis''-retinal configuration, which — upon capturing a [[photon]] of the correct wavelength — straightens out into an all-''trans''-retinal configuration. This configuration change pushes against an opsin protein in the [[retina]], which triggers a chemical signaling cascade, which results in [[perception]] of light or images by the brain. The absorbance spectrum of the chromophore depends on its interactions with the opsin protein to which it is bound, so that different retinal-opsin complexes will absorb photons of different wavelengths (i.e., different colors of light).

===Opsins===
[[File:1415_Retinal_Isomers.jpg|thumb|An opsin protein surrounds a molecule of 11-''cis'' retinal, awaiting the arrival of a photon. Once the retinal molecule captures a photon, its configuration change causes it to push against the surrounding opsin protein which may cause the opsin to send a chemical signal to the brain indicating that light has been detected. Retinal is then converted back to its 11-''cis'' configuration by ATP phosphorylation, and the cycle begins again.]]
[[File:Rhodopsin-transducin.png|thumb|left|Animal GPCR [[rhodopsin]] (rainbow-colored) embedded in a [[lipid bilayer]] (heads red and tails blue) with [[transducin]] below it. G<sub>t</sub>α is colored red, G<sub>t</sub>β blue, and G<sub>t</sub>γ yellow. There is a bound [[guanosine diphosphate|GDP]] molecule in the G<sub>t</sub>α-subunit and a bound '''retinal''' (black) in the rhodopsin. The [[amino-terminus|N-terminus]] terminus of rhodopsin is red and the [[C-terminus]] blue. Anchoring of transducin to the membrane has been drawn in black.]]

Retinal is bound to [[opsin]]s, which are [[G protein-coupled receptor]]s (GPCRs).<ref name=Casey1988>{{cite journal |last1=Casey |first1=P J |last2=Gilman |first2=A G |title=G protein involvement in receptor-effector coupling. |journal=Journal of Biological Chemistry |date=February 1988 |volume=263 |issue=6 |pages=2577–2580 |doi=10.1016/s0021-9258(18)69103-3 |pmid=2830256|s2cid=38970721 |doi-access=free }}</ref><ref name=Attwood1994>{{cite journal |last1=Attwood |first1=T. K. |last2=Findlay |first2=J. B. C. |title=Fingerprinting G-protein-coupled receptors |journal=Protein Engineering, Design and Selection |date=1994 |volume=7 |issue=2 |pages=195–203 |doi=10.1093/protein/7.2.195|pmid=8170923 }}</ref> Opsins, like other GPCRs, have seven transmembrane [[alpha-helix|alpha-helices]] connected by six loops. They are found in the [[photoreceptor cell]]s in the [[retina]] of eye. The opsin in the vertebrate [[rod cell]]s is [[rhodopsin]]. The rods form disks, which contain the rhodopsin molecules in their membranes and which are entirely inside of the cell. The [[N-terminus]] head of the molecule extends into the interior of the disk, and the [[C-terminus]] tail extends into the cytoplasm of the cell. The opsins in the [[cone cell]]s are [[OPN1SW]], [[OPN1MW]], and [[OPN1LW]]. The cones form incomplete disks that are part of the [[plasma membrane]], so that the N-terminus head extends outside of the cell. In opsins, retinal binds covalently to a [[lysine]]<ref>{{cite journal |last1=Bownds |first1=Deric |title=Site of Attachment of Retinal in Rhodopsin |journal=Nature |date=December 1967 |volume=216 |issue=5121 |pages=1178–1181 |doi=10.1038/2161178a0 |pmid=4294735|bibcode=1967Natur.216.1178B |s2cid=1657759 }}</ref> in the seventh transmembrane helix<ref>{{cite journal |last1=Hargrave |first1=P. A. |last2=McDowell |first2=J. H. |last3=Curtis |first3=Donna R. |last4=Wang |first4=Janet K. |last5=Juszczak |first5=Elizabeth |last6=Fong |first6=Shao-Ling |last7=Mohana Rao |first7=J. K. |last8=Argos |first8=P. |title=The structure of bovine rhodopsin |journal=Biophysics of Structure and Mechanism |date=1983 |volume=9 |issue=4 |pages=235–244 |doi=10.1007/BF00535659 |pmid=6342691|s2cid=20407577 }}</ref><ref name=Palczewski2000>{{cite journal | vauthors = Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M | display-authors = 6 | title = Crystal structure of rhodopsin: A G protein-coupled receptor | journal = Science | volume = 289 | issue = 5480 | pages = 739–45 | date = August 2000 | pmid = 10926528 | doi = 10.1126/science.289.5480.739 | citeseerx = 10.1.1.1012.2275 | bibcode = 2000Sci...289..739P }}</ref><ref name=Murakami2008>{{cite journal | vauthors = Murakami M, Kouyama T | title = Crystal structure of squid rhodopsin | journal = Nature | volume = 453 | issue = 7193 | pages = 363–7 | date = May 2008 | pmid = 18480818 | doi = 10.1038/nature06925 | bibcode = 2008Natur.453..363M | s2cid = 4339970 }}</ref> through a [[Schiff base]].<ref>{{cite journal |last1=Collins |first1=F. D. |title=Rhodopsin and Indicator Yellow |journal=Nature |date=March 1953 |volume=171 |issue=4350 |pages=469–471 |doi=10.1038/171469a0 |pmid=13046517|bibcode=1953Natur.171..469C |s2cid=4152360 }}</ref><ref>{{cite journal |last1=Pitt |first1=G. A. J. |last2=Collins |first2=F. D. |last3=Morton |first3=R. A. |last4=Stok |first4=Pauline |title=Studies on rhodopsin. 8. Retinylidenemethylamine, an indicator yellow analogue |journal=Biochemical Journal |date=1 January 1955 |volume=59 |issue=1 |pages=122–128 |doi=10.1042/bj0590122 |pmid=14351151|pmc=1216098 }}</ref> Forming the Schiff base linkage involves removing the oxygen atom from retinal and two hydrogen atoms from the free amino group of lysine, giving H<sub>2</sub>O. Retinylidene is the divalent group formed by removing the oxygen atom from retinal, and so opsins have been called [[retinylidene protein]]s.

Opsins are prototypical [[G protein-coupled receptor]]s (GPCRs).<ref>{{cite journal |last=Lamb |first=T D |year=1996 |title=Gain and kinetics of activation in the G-protein cascade of phototransduction |journal=Proceedings of the National Academy of Sciences |volume=93 |issue=2 |pages=566–570 |pmid=8570596 |doi=10.1073/pnas.93.2.566 |pmc=40092 |bibcode=1996PNAS...93..566L|doi-access=free }}</ref> Cattle rhodopsin, the opsin of the rod cells, was the first GPCR to have its [[Protein primary structure|amino acid sequence]]<ref name=Ovchinnikov1982>{{cite journal |last1=Ovchinnikov |first1=Yu.A. |title=Rhodopsin and bacteriorhodopsin: structure-function relationships |journal=FEBS Letters |date=8 November 1982 |volume=148 |issue=2 |pages=179–191 |doi=10.1016/0014-5793(82)80805-3 |pmid=6759163|s2cid=85819100 |doi-access=free |bibcode=1982FEBSL.148..179O }}</ref> and [[Protein tertiary structure|3D-structure]] (via [[X-ray crystallography]]) determined.<ref name="Palczewski2000" />  [[Cattle]] rhodopsin contains 348 [[amino acid]] residues. Retinal binds as chromophore at Lys<sup>296</sup>.<ref name="Palczewski2000" /><ref name=Ovchinnikov1982 /> This lysine is conserved in almost all opsins, only a few opsins have lost it during [[evolution]].<ref name=Guehmann2022>{{cite journal | vauthors = Gühmann M, Porter ML, Bok MJ | title = The Gluopsins: Opsins without the Retinal Binding Lysine | journal = Cells | volume = 11 | issue = 15 | pages = 2441 | date = August 2022 | pmid = 35954284 | doi = 10.3390/cells11152441 | pmc = 9368030 | doi-access = free }}</ref> Opsins without the retinal binding lysine are not light sensitive.<ref name=Katana2019>{{cite journal |last1=Katana |first1=Radoslaw |last2=Guan |first2=Chonglin |last3=Zanini |first3=Damiano |last4=Larsen |first4=Matthew E. |last5=Giraldo |first5=Diego |last6=Geurten |first6=Bart R.H. |last7=Schmidt |first7=Christoph F. |last8=Britt |first8=Steven G. |last9=Göpfert |first9=Martin C. |title=Chromophore-Independent Roles of Opsin Apoproteins in Drosophila Mechanoreceptors |journal=Current Biology |date=September 2019 |volume=29 |issue=17 |pages=2961–2969.e4 |doi=10.1016/j.cub.2019.07.036 |pmid=31447373|s2cid=201420079 |doi-access=free |bibcode=2019CBio...29E2961K }}</ref><ref name=Leung2020>{{cite journal |last1=Leung |first1=Nicole Y. |last2=Thakur |first2=Dhananjay P. |last3=Gurav |first3=Adishthi S. |last4=Kim |first4=Sang Hoon |last5=Di Pizio |first5=Antonella |last6=Niv |first6=Masha Y. |last7=Montell |first7=Craig |title=Functions of Opsins in Drosophila Taste |journal=Current Biology |date=April 2020 |volume=30 |issue=8 |pages=1367–1379.e6 |doi=10.1016/j.cub.2020.01.068 |pmid=32243853|pmc=7252503 |bibcode=2020CBio...30E1367L }}</ref><ref>{{cite journal | vauthors = Kumbalasiri T, Rollag MD, Isoldi MC, Castrucci AM, Provencio I | title = Melanopsin triggers the release of internal calcium stores in response to light | journal = Photochemistry and Photobiology | volume = 83 | issue = 2 | pages = 273–279 | date = March 2007 | pmid = 16961436 | doi = 10.1562/2006-07-11-RA-964 | s2cid = 23060331 }}</ref> Such opsins may have other functions.<ref name=Leung2020 /><ref name=Guehmann2022 />

Although mammals use retinal exclusively as the opsin chromophore, other groups of animals additionally use four chromophores closely related to retinal: 3,4-didehydroretinal (vitamin A<sub>2</sub>), (3''R'')-3-hydroxyretinal, (3''S'')-3-hydroxyretinal (both vitamin A<sub>3</sub>), and (4''R'')-4-hydroxyretinal (vitamin A<sub>4</sub>). Many fish and amphibians use 3,4-didehydroretinal, also called [[dehydroretinal]]. With the exception of the [[diptera]]n suborder [[Cyclorrhapha]] (the so-called higher flies), all [[insect]]s examined use the (''R'')-[[enantiomer]] of 3-hydroxyretinal. The (''R'')-enantiomer is to be expected if 3-hydroxyretinal is produced directly from [[xanthophyll]] carotenoids. Cyclorrhaphans, including ''[[Drosophila]]'', use (3''S'')-3-hydroxyretinal.<ref>{{cite journal |last1=Seki |first1=Takaharu |last2=Isono |first2=Kunio |last3=Ito |first3=Masayoshi |last4=Katsuta |first4=Yuko |year=1994 |title=Flies in the Group Cyclorrhapha Use (3S)-3-Hydroxyretinal as a Unique Visual Pigment Chromophore |journal=European Journal of Biochemistry |volume=226 |issue=2 |pages=691–696 |doi=10.1111/j.1432-1033.1994.tb20097.x |pmid=8001586 |doi-access=}}</ref><ref>{{cite journal |last1=Seki |first1=Takaharu |last2=Isono |first2=Kunio |last3=Ozaki |first3=Kaoru |last4=Tsukahara |first4=Yasuo |last5=Shibata-Katsuta |first5=Yuko |last6=Ito |first6=Masayoshi |last7=Irie |first7=Toshiaki |last8=Katagiri |first8=Masanao |year=1998 |title=The metabolic pathway of visual pigment chromophore formation in Drosophila melanogaster: All-trans (3S)-3-hydroxyretinal is formed from all-trans retinal via (3R)-3-hydroxyretinal in the dark |journal=European Journal of Biochemistry |volume=257 |issue=2 |pages=522–527 |doi=10.1046/j.1432-1327.1998.2570522.x |pmid=9826202 |doi-access=free}}</ref> [[Firefly squid]] have been found to use (4''R'')-4-hydroxyretinal.
{{Clear}}

===Visual cycle===
{{main|Visual cycle}}
[[File:Visual cycle.svg|thumb|right|350x350px|Visual cycle]]
The visual cycle is a circular [[enzymatic pathway]], which is the front-end of phototransduction. It regenerates 11-''cis''-retinal. For example, the visual cycle of mammalian rod cells is as follows:
#[[all-trans-retinyl ester|all-''trans''-retinyl ester]] + H<sub>2</sub>O → 11-''cis''-retinol + [[fatty acid]]; [[RPE65]] isomerohydrolases;<ref>{{cite journal |last1=Moiseyev |first1=Gennadiy |last2=Chen |first2=Ying |last3=Takahashi |first3=Yusuke |last4=Wu |first4=Bill X. |last5=Ma |first5=Jian-xing |year=2005 |title=RPE65 is the isomerohydrolase in the retinoid visual cycle |journal=Proceedings of the National Academy of Sciences |volume=102 |issue=35 |pages=12413–12418 |doi=10.1073/pnas.0503460102 |pmid=16116091 |pmc=1194921 |bibcode=2005PNAS..10212413M|doi-access=free }}</ref>
#[[11-cis-retinol|11-''cis''-retinol]] + NAD<sup>+</sup> → 11-''cis''-retinal + NADH + H<sup>+</sup>; 11-''cis''-retinol dehydrogenases;
#[[11-cis retinal|11-''cis''-retinal]] + [[aporhodopsin]] → [[rhodopsin]] + H<sub>2</sub>O; forms [[Schiff base]] linkage to [[lysine]], -CH=N<sup>+</sup>H-;
#rhodopsin + [[photon|hν]] → [[metarhodopsin]] II (i.e., 11-''cis'' [[photoisomerization|photoisomerizes]] to all-''trans''):
#:(rhodopsin + hν → photorhodopsin → bathorhodopsin → lumirhodopsin → metarhodopsin I → metarhodopsin II);
#[[metarhodopsin]] II + H<sub>2</sub>O → aporhodopsin + all-''trans''-retinal;
#[[all-trans-retinal|all-''trans''-retinal]] + NADPH + H<sup>+</sup> → all-''trans''-retinol + NADP<sup>+</sup>; all-''trans''-retinol [[dehydrogenase]]s;
#all-''trans''-retinol + fatty acid → all-''trans''-retinyl ester + H<sub>2</sub>O; [[lecithin retinol acyltransferase]]s (LRATs).<ref>{{cite journal |last1=Jin |first1=Minghao |last2=Yuan |first2=Quan |last3=Li |first3=Songhua |last4=Travis |first4=Gabriel H. |year=2007 |title=Role of LRAT on the Retinoid Isomerase Activity and Membrane Association of Rpe65 |journal=Journal of Biological Chemistry |volume=282 |issue=29 |pages=20915–20924 |doi=10.1074/jbc.M701432200 |pmid=17504753 |pmc=2747659|doi-access=free }}</ref>

Steps 3, 4, 5, and 6 occur in [[rod cell|rod cell outer segments]]; Steps 1, 2, and 7 occur in [[retinal pigment epithelium]] (RPE) cells.

RPE65 isomerohydrolases are [[homology (biology)|homologous]] with beta-carotene monooxygenases;<ref name="von Lintig"/> the homologous ninaB enzyme in ''Drosophila'' has both retinal-forming carotenoid-oxygenase activity and all-''trans'' to 11-''cis'' isomerase activity.<ref name="Oberhauser08">{{cite journal |last1=Oberhauser |first1=Vitus |last2=Voolstra |first2=Olaf |last3=Bangert |first3=Annette |last4=von Lintig |first4=Johannes |last5=Vogt |first5=Klaus |year=2008 |title=NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=48 |pages=19000–5 |doi=10.1073/pnas.0807805105 |pmid=19020100 |pmc=2596218 |bibcode=2008PNAS..10519000O|doi-access=free }}</ref>

==Microbial rhodopsins==
{{Main article|Microbial rhodopsin}}
All-''trans''-retinal is also an essential component of [[microbial]] opsins such as [[bacteriorhodopsin]], [[channelrhodopsin]], and [[halorhodopsin]], which are important in [[bacteria]]l and [[archaea]]l [[anoxygenic photosynthesis]].  In these molecules, light causes the all-''trans''-retinal to become 13-''cis'' retinal, which then cycles back to all-''trans''-retinal in the dark state. These proteins are not evolutionarily related to animal opsins and are not GPCRs; the fact that they both use retinal is a result of [[convergent evolution]].<ref name=13CIS>{{cite journal |doi=10.1016/S1011-1344(02)00245-2 |pmid=11960728 |title=All-trans to 13-cis retinal isomerization in light-adapted bacteriorhodopsin at acidic pH |year=2002 |last1=Chen |first1=De-Liang |last2=Wang |first2=Guang-yu |last3=Xu |first3=Bing |last4=Hu |first4=Kun-Sheng |journal=Journal of Photochemistry and Photobiology B: Biology |volume=66 |issue=3 |pages=188–194|bibcode=2002JPPB...66..188C }}</ref>

==History==
The American biochemist [[George Wald]] and others had outlined the visual cycle by 1958. For his work, Wald won a share of the 1967 [[Nobel Prize in Physiology or Medicine]] with [[Haldan Keffer Hartline]] and [[Ragnar Granit]].<ref>[https://www.nobelprize.org/prizes/medicine/1967/summary/ Nobel Prize in Physiology or Medicine 1967]</ref>

==See also==
*[[Purple Earth hypothesis]]
*[[Sensory nervous system]]
*[[Visual perception]]
*[[Visual phototransduction]]

==References==
{{Reflist}}

==Further reading==
{{Refbegin}}
*{{cite journal |last=Fernald |first=Russell D. |year=2006 |title=Casting a Genetic Light on the Evolution of Eyes |journal=Science |volume=313 |issue=5795 |pages=1914–1918 |doi=10.1126/science.1127889 |pmid=17008522 |bibcode=2006Sci...313.1914F |s2cid=84439732}}
*{{cite journal |last1=Amora |first1=Tabitha L. |last2=Ramos |first2=Lavoisier S. |last3=Galan |first3=Jhenny F. |last4=Birge |first4=Robert R. |year=2008 |title=Spectral Tuning of Deep Red Cone Pigments |journal=Biochemistry |volume=47 |issue=16 |pages=4614–20 |pmid=18370404 |doi=10.1021/bi702069d |pmc=2492582}}
*{{cite journal |last1=Barlow |first1=H.B. |last2=Levick |first2=W.R. |last3=Yoon |first3=M. |year=1971 |title=Responses to single quanta of light in retinal ganglion cells of the cat |journal=Vision Research |volume=11 |issue=Supplement 3 |pages=87–101 |doi=10.1016/0042-6989(71)90033-2 |pmid=5293890}}
*{{cite journal |last1=Baylor |first1=D A |last2=Lamb |first2=T D |last3=Yau |first3=K W |year=1979 |title=Responses of retinal rods to single photons |journal=Journal of Physiology |volume=288 |pages=613–634 |pmid=112243 |doi=10.1113/jphysiol.1979.sp012716 |pmc=1281447 }}
*{{cite journal |last1=Fan |first1=Jie |last2=Woodruff |first2=Michael L |last3=Cilluffo |first3=Marianne C |last4=Crouch |first4=Rosalie K |last5=Fain |first5=Gordon L |year=2005 |title=Opsin activation of transduction in the rods of dark-reared Rpe65 knockout mice |journal=Journal of Physiology |volume=568 |issue=1 |pages=83–95 |doi=10.1113/jphysiol.2005.091942 |pmid=15994181 |pmc=1474752}}
*{{cite journal |last1=Hecht |first1=Selig |last2=Shlaer |first2=Simon |last3=Pirenne |first3=Maurice Henri |year=1942 |journal=Journal of General Physiology |volume=25 |issue=6 |pages=819–840 |doi=10.1085/jgp.25.6.819 |pmid=19873316 |pmc=2142545 |title=Energy, Quanta, and Vision}}
*{{cite journal |last1=Kawaguchi |first1=Riki |last2=Yu |first2=Jiamei |last3=Honda |first3=Jane |last4=Hu |first4=Jane |last5=Whitelegge |first5=Julian |last6=Ping |first6=Peipei |last7=Wiita |first7=Patrick |last8=Bok |first8=Dean |last9=Sun |first9=Hui |year=2007 |title=A Membrane Receptor for Retinol Binding Protein Mediates Cellular Uptake of Vitamin A |journal=Science |volume=315 |issue=5813 |pages=820–825 |doi=10.1126/science.1136244 |pmid=17255476 |bibcode=2007Sci...315..820K |s2cid=25258551|doi-access=free }}
*{{cite journal |last1=Kloer |first1=Daniel P. |last2=Ruch |first2=Sandra |last3=Al-Babili |first3=Salim |last4=Beyer |first4=Peter |last5=Schulz |first5=Georg E. |year=2005 |title=The Structure of a Retinal-Forming Carotenoid Oxygenase |journal=Science |volume=308 |issue=5719 |pages=267–269 |doi=10.1126/science.1108965 |pmid=15821095 |bibcode=2005Sci...308..267K |s2cid=6318853 }}
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*{{cite journal |last1=Prado-Cabrero |first1=Alfonso |last2=Scherzinger |first2=Daniel |last3=Avalos |first3=Javier |last4=Al-Babili |first4=Salim |year=2007 |title=Retinal Biosynthesis in Fungi: Characterization of the Carotenoid Oxygenase CarX from Fusarium fujikuroi |journal=[[Eukaryotic Cell (journal)|Eukaryotic Cell]] |volume=6 |issue=4 |pages=650–657 |doi=10.1128/EC.00392-06 |pmid=17293483 |pmc=1865656}}
*{{cite journal |last1=Racker |first1=Efraim |last2=Stoeckenius |first2=Walther |year=1974 |title=Reconstitution of Purple Membrane Vesicles Catalyzing Light-driven Proton Uptake and Adenosine Triphosphate Formation |journal=Journal of Biological Chemistry |volume=249 |issue=2 |pages=662–663 |doi=10.1016/S0021-9258(19)43080-9 |pmid=4272126 |doi-access=free}}
*{{cite journal |last1=Sadekar |first1=Sumedha |last2=Raymond |first2=Jason|author3-link=Robert E. Blankenship |last3=Blankenship |first3=Robert E. |year=2006 |title=Conservation of Distantly Related Membrane Proteins: Photosynthetic Reaction Centers Share a Common Structural Core |journal=Molecular Biology and Evolution |volume=23 |issue=11 |pages=2001–2007 |doi=10.1093/molbev/msl079 |pmid=16887904 |doi-access=}}
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*{{cite journal |last1=Schäfer |first1=Günter |last2=Engelhard |first2=Martin |last3=Müller |first3=Volker |year=1999 |title=Bioenergetics of the Archaea |journal=Microbiology and Molecular Biology Reviews |volume=63 |issue=3 |pages=570–620 |pmid=10477309 |doi=10.1128/MMBR.63.3.570-620.1999 |pmc=103747}}
*{{cite journal |last1=Schmidt |first1=Holger |last2=Kurtzer |first2=Robert |last3=Eisenreich |first3=Wolfgang |last4=Schwab |first4=Wilfried |year=2006 |title=The Carotenase AtCCD1 from Arabidopsis thaliana Is a Dioxygenase |journal=Journal of Biological Chemistry |volume=281 |issue=15 |pages=9845–9851 |doi=10.1074/jbc.M511668200 |pmid=16459333 |doi-access=free}}
*{{cite journal |last1=Send |first1=Robert |last2=Sundholm |first2=Dage |year=2007 |title=Stairway to the conical intersection: A computational study of retinal isomerization |journal=Journal of Physical Chemistry A |volume=111 |issue=36 |pages=8766–8773 |doi=10.1021/jp073908l |pmid=17713894 |bibcode=2007JPCA..111.8766S}}
*{{cite journal |last1=Su |first1=Chih-Ying |last2=Luo |first2=Dong-Gen |last3=Terakita |first3=Akihisa |last4=Shichida |first4=Yoshinori |last5=Liao |first5=Hsi-Wen |last6=Kazmi |first6=Manija A. |last7=Sakmar |first7=Thomas P. |last8=Yau |first8=King-Wai |year=2006 |title=Parietal-Eye Phototransduction Components and Their Potential Evolutionary Implications |journal=Science |volume=311 |issue=5767 |pages=1617–1621 |doi=10.1126/science.1123802 |pmid=16543463 |bibcode=2006Sci...311.1617S |s2cid=28604455 }}
*{{cite journal |last1=Venter |first1=J. Craig |last2=Remington |author-link=Craig Venter |year=2004 |title=Environmental Genome Shotgun Sequencing of the Sargasso Sea |journal=Science |volume=304 |issue=5667 |pages=66–74 |doi=10.1126/science.1093857 |pmid=15001713 |first2=K |last3=Heidelberg |first3=JF |last4=Halpern |first4=AL |last5=Rusch |first5=D |last6=Eisen |first6=JA |last7=Wu |first7=D |last8=Paulsen |first8=I |last9=Nelson |first9=KE |last10=Nelson |first10=W |last11=Fouts |first11=D. E. |last12=Levy |first12=S |last13=Knap |first13=A. H. |last14=Lomas |first14=M. W. |last15=Nealson |first15=K |last16=White |first16=O |last17=Peterson |first17=J |last18=Hoffman |first18=J |last19=Parsons |first19=R |last20=Baden-Tillson |first20=H |last21=Pfannkoch |first21=C |last22=Rogers |first22=Y. H. |last23=Smith |first23=H. O. |bibcode=2004Sci...304...66V |display-authors=8 |citeseerx=10.1.1.124.1840 |s2cid=1454587}} The oceans are full of type 1 rhodopsin.
*{{cite journal |last1=Wang |first1=Tao |last2=Jiao |first2=Yuchen |last3=Montell |first3=Craig |year=2007 |title=Dissection of the pathway required for generation of vitamin A and for Drosophila phototransduction |journal=Journal of Cell Biology |volume=177 |issue=2 |pages=305–316 |doi=10.1083/jcb.200610081 |pmid=17452532 |pmc=2064138}}
*{{cite journal |last1=Waschuk |first1=Stephen A. |last2=Bezerra |first2=Arandi G. |last3=Shi |first3=Lichi |last4=Brown |first4=Leonid S. |year=2005 |title=Leptosphaeria rhodopsin: Bacteriorhodopsin-like proton pump from a eukaryote |journal=Proceedings of the National Academy of Sciences |volume=102 |issue=19 |pages=6879–6883 |doi=10.1073/pnas.0409659102 |pmid=15860584 |pmc=1100770 |bibcode=2005PNAS..102.6879W|doi-access=free }}
*{{cite journal |last1=Yokoyama |first1=Shozo |last2=Radlwimmer |first2=F. Bernhard |year=2001 |title=The molecular genetics and evolution of red and green color vision in vertebrates |journal=Genetics |volume=158 |issue=4 |pages=1697–1710 |doi=10.1093/genetics/158.4.1697 |pmid=11545071 |pmc=1461741}}
*{{cite book |editor-last=Briggs |editor-first=Winslow R. |editor2-last=Spudich |editor2-first=John L. |title=Handbook of Photosensory Receptors |year=2005 |publisher=Wiley |isbn=978-3-527-31019-7}}
*{{cite web |url=https://www.nobelprize.org/uploads/2018/06/wald-lecture.pdf |title=Nobel Lecture: The Molecular Basis of Visual Excitation |access-date=2009-02-23 |last=Wald |first=George |author-link=George Wald |year=1967}}
{{Refend}}

==External links==
*[http://www.accessexcellence.org/AE/AEC/CC/vision_background.html First Steps of Vision] - National Health Museum
*[http://www.chemistry.wustl.edu/~edudev/LabTutorials/Vision/Vision.html Vision and Light-Induced Molecular Changes]
*[https://palaeo-electronica.org/2000_1/retinal/vision.htm Retinal Anatomy and Visual Capacities]
*[https://www.ch.ic.ac.uk/vchemlib/mim/bristol/retinal/retinal_text.htm Retinal], Imperial College v-chemlib

{{Carotenoids}}
{{Authority control}}

[[Category:Aldehydes]]
[[Category:Apocarotenoids]]
[[Category:Cyclohexenes]]
[[Category:Photosynthetic pigments]]
[[Category:Signal transduction]]
[[Category:Vision]]
[[Category:Vitamin A]]

[[he:אופסין#רטינל]]