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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration.
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The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration.

机译：视黄酸与RPE65的特异性结合以及黄斑变性的治疗方法。

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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 represent an important approach to reducing the accumulation of the retinotoxic lipofuscin by inhibiting visual cycle function. The identification of RPE65 as the visual cycle target for the retinoic acids makes it feasible to develop useful drugs to treat retinal and macular degeneration while avoiding the substantial side effects of the retinoic acids.
机译：RPE65在视觉循环的操作中必不可少，并且可充当全反式视黄酯的伴侣，后者是视觉循环中异构化的底物。 RPE65立体特异性地以47 nM的K（D）结合全反式维甲酸酯。通过定量荧光技术可以看出，用于治疗痤疮但引起夜盲症的Accutane（13-顺-视黄酸）以195 nM的K（D）与RPE65结合。全反式维甲酸结合的K（D）为109 nM。视黄酸与RPE65的结合与全反式视黄酯的结合具有竞争性，这种竞争抑制了视觉循环功能。与RPE65弱结合的视黄酸类似物没有抑制作用。这些数据表明RPE65功能是视觉循环功能的速率限制。他们还揭示了视黄酸诱导夜盲症的目标。最后，某些形式的视网膜和黄斑变性是由基于维生素A的视黄醛产品（称为视黄素色素上皮-脂褐素）的积累引起的。这些视黄醛产物在视力循环操作后视紫红质漂白和再生的正常过程中积累。诸如Accutane之类的药物可能代表了通过抑制视觉循环功能来减少视黄醛脂褐素积累的重要方法。 RPE65作为视黄酸的视觉周期靶标的鉴定使得开发有用的药物来治疗视网膜和黄斑变性，同时避免了视黄酸的实质性副作用成为可能。

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