of animals additionally use four chromophores closely related to retinal: 3,4-didehydroretinal (vitamin A2), (3R)-3-hydroxyretinal, (3S)-3-hydroxyretinal (both vitamin A3), and (4R)-4-hydroxyretinal (vitamin A4). Many fish and amphibians use 3,4-didehydroretinal, also called dehydroretinal. With the exception of the dipteran suborder Cyclorrhapha (the so-called higher flies), all insects 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 (3S)-3-hydroxyretinal. Firefly squid have been found to use (4R)-4-hydroxyretinal. 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 + H2O → 11-cis-retinol + fatty acid; RPE65 isomerohydrolases; 11-cis-retinol + NAD+ → 11-cis-retinal + NADH + H+; 11-cis-retinol dehydrogenases; 11-cis-retinal + aporhodopsin → rhodopsin + H2O; forms Schiff base linkage to lysine, -CH=N+H-; rhodopsin + hν → metarhodopsin II (i.e., 11-cis photoisomerizes to all-trans): (rhodopsin + hν → photorhodopsin → bathorhodopsin → lumirhodopsin → metarhodopsin I → metarhodopsin II); metarhodopsin II + H2O → aporhodopsin + all-trans-retinal; all-trans-retinal + NADPH + H+ → all-trans-retinol + NADP+; all-trans-retinol dehydrogenases; all-trans-retinol + fatty acid → all-trans-retinyl ester + H2O; lecithin retinol acyltransferases (LRATs). Steps 3, 4, 5, and 6 occur in rod cell outer segments; Steps 1, 2, and 7 occur in retinal pigment epithelium (RPE) cells. RPE65 isomerohydrolases are homologous with beta-carotene monooxygenases; the homologous ninaB enzyme in Drosophila has both retinal-forming carotenoid-oxygenase activity and all-trans to 11-cis isomerase activity. Microbial rhodopsins All-trans-retinal is also an essential component of microbial opsins such as bacteriorhodopsin, channelrhodopsin, and halorhodopsin. 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. 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. See also Purple Earth hypothesis Sensory nervous system Visual perception Visual phototransduction References Further reading Good historical review. The oceans are full of type 1 rhodopsin. External links First Steps of Vision - National Health Museum Vision and Light-Induced Molecular Changes Retinal Anatomy and Visual Capacities Retinal,