The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration

Proceedings of the National Academy of Sciences of the United States of America
Deviprasad Gollapalli, R R Rando

Abstract

RPE65 is essential in the operation of the visual cycle and functions as a chaperone for all-trans-retinyl esters, the substrates for isomerization in the visual cycle. RPE65 stereospecifically binds all-trans-retinyl esters with a K(D) of 47 nM. It is shown here by using a quantitative fluorescence technique, that Accutane (13-cis-retinoic acid), a drug used in the treatment of acne but that causes night blindness, binds to RPE65 with a K(D) of 195 nM. All-trans-retinoic acid binds with a K(D) of 109 nM. The binding of the retinoic acids to RPE65 is competitive with all-trans-retinyl ester binding, and this competition inhibits visual cycle function. A retinoic acid analog that binds weakly to RPE65 is not inhibitory. These data suggest that RPE65 function is rate-limiting in visual cycle function. They also reveal the target through which the retinoic acids induce night blindness. Finally, certain forms of retinal and macular degeneration are caused by the accumulation of vitamin A-based retinotoxic products, called the retinyl pigment epithelium-lipofuscin. These retinotoxic products accumulate during the normal course of rhodopsin bleaching and regeneration after the operation of the visual cycle. Drugs such as Accutane may...Continue Reading

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Citations

Nov 26, 2013·Chemical Reviews·Rosana ÁlvarezÁngel R de Lera
Jul 9, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Nilanjana SenguptaJeffrey R Harris
Jan 16, 2008·The Journal of Biological Chemistry·Marcin GolczakKrzysztof Palczewski
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Aug 27, 2005·Photochemistry and Photobiology·Małgorzata Rózanowska, Tadeusz Sarna

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