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

Gollapalli, Deviprasad R.; Rando, Robert R.

doi:10.1073/pnas.0401936101

Cited by 49Retinal Development and DisordersRetinoids in leukemia and cellular processesRetinal Diseases and Treatments

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

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Gollapalli, Deviprasad R., Rando, Robert R.·2004·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0401936101PMC PMC454159

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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 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.

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Isotretinoin reduces the accumulation of toxic byproducts of the visual cycle, such as A2E.
“However, on the other hand, it reduces the accumulation of toxic byproducts of the visual cycle, such as N-retinyl-N-retinylidene ethanolamine (A2E) [16,17,18].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [16]
In the RPE, isotretinoin inhibits two key visual cycle enzymes, RPE65 and 11-cis-retinol dehydrogenase.
“In retina in the retinal pigment epithelium (RPE), isotretinoin inhibits two key visual cycle enzymes, RPE-specific 65 kDa protein (RPE65) [16] and 11-cis-retinol dehydrogenase [17,18] (Figure 1).”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [16]
Isotretinoin impairs the chromophore 11-cis-retinal and slows rhodopsin regeneration, which can cause night blindness.
“This impairs chromophore, 11-cis-retinal, and slows rhodopsin (RHO) regeneration which can cause night blindness.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [16]

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Self-citation

Authors: Gollapalli, D. R., & Rando, R. R.
Affiliations: Harvard University (US)
Corresponding author: Rando, Robert R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2004-06-24
Volume: 101
Issue: 27
Pages: 10030-10035
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0401936101
PMC: PMC454159
OpenAlex: W2066823591
Cited by: 49
References: 32
Citations by year: 2025: 3 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2016: 2 · 2015: 2 · 2013: 4 · 2012: 4
FWCI: 2.02
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Eye Institute (R01EY004096, EY-04096, R37EY004096)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Keywords: RPE65, retinoic acid binding, visual cycle, isotretinoin, night blindness, lipofuscin accumulation, retinal degeneration, macular degeneration, rhodopsin regeneration, competitive binding
MeSH terms: Retinyl Esters, Animals, Cattle, Diterpenes, Eye Proteins, Macular Degeneration, Proteins, Tretinoin, Vitamin A

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

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