Retinoid cycle and synthesis of A2E. Light triggers isomerization of 11-cis-retinal (11-cis-RAL) chromophore to all-trans-retinal (All-trans-RAL). Under normal conditions, all-trans-retinal is reduced to all-trans-retinol (All-trans-ROL) by retinol dehydrogenases 8 and 12 (RDH8 and RDH12, respectively), which then is esterified by lecithin retinol acyltransferase (LRAT) to all-trans-retinyl esters (All-trans-retinyl-RE). These esters can be stored in retinosomes or converted to 11-cis-retinol (11-cis-ROL) by retinal pigment epithelium-specific protein 65 (RPE65) isomerase. 11-cis-Retinol is converted to 11-cis-retinal by retinol dehydrogenase 5 (RDH5), which then can re-associate with opsin forming the visual pigment, rhodopsin. Inefficient reduction of all-trans-retinal to all-trans-retinol results in excess of all-trans-retinal, which can react with phosphatidylethanolamine (PE), resulting in formation of bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E). Accumulated A2E causes an increase of reactive oxygen species (ROS) detrimental to the retinal cells. Overproduction of ROS can be decreased by specific retinoid analogs, dietary carotenoids and polyphenolics, particularly flavonoids. (A color version of this figure is available in the online journal.)