Retinal pigment epithelium 65 kDa protein (RPE65): An update. (May 2022)

• Record Type: Journal Article
• Authors: Kiser, Philip D.
• Is Part Of: Progress in retinal and eye research. Volume 88(2022)
• Publication Date: 2022-05
• Subjects: Retinal pigment epithelium -- Visual cycle -- Isomerase -- Isomerohydrolase -- Non-heme iron enzyme -- Photoreceptors -- Inhibitor -- Carbocation; Retina -- Periodicals; Retina -- Research -- Methodology -- Periodicals; Eye -- Diseases -- Periodicals; Eye -- Periodicals; Eye Diseases -- Periodicals; Retina -- Periodicals; Rétine -- Périodiques; Rétine -- Recherche -- Méthodologie -- Périodiques; 617.7005
• DOI: 10.1016/j.preteyeres.2021.101013
• Languages: English
• ISSNs: 1350-9462

Abstract

Abstract: Vertebrate vision critically depends on an 11- cis -retinoid renewal system known as the visual cycle. At the heart of this metabolic pathway is an enzyme known as retinal pigment epithelium 65 kDa protein (RPE65), which catalyzes an unusual, possibly biochemically unique, reaction consisting of a coupled all- trans -retinyl ester hydrolysis and alkene geometric isomerization to produce 11- cis -retinol. Early work on this isomerohydrolase demonstrated its membership to the carotenoid cleavage dioxygenase superfamily and its essentiality for 11- cis -retinal production in the vertebrate retina. Three independent studies published in 2005 established RPE65 as the actual isomerohydrolase instead of a retinoid-binding protein as previously believed. Since the last devoted review of RPE65 enzymology appeared in this journal, major advances have been made in a number of areas including our understanding of the mechanistic details of RPE65 isomerohydrolase activity, its phylogenetic origins, the relationship of its membrane binding affinity to its catalytic activity, its role in visual chromophore production for rods and cones, its modulation by macromolecules and small molecules, and the involvement of RPE65 mutations in the development of retinal diseases. In this article, I will review these areas of progress with the goal of integrating results from the varied experimental approaches to provide a comprehensive picture of RPE65 biochemistry. Key outstanding questions that may prove to be fruitful future research pursuits will also be highlighted. Highlights: Relationships of RPE65 to carotenoid cleavage dioxygenases have been further elucidated. The mechanism of the RPE65-catalyzed isomerohydrolase reaction has been clarified. Potent small molecule and protein modulators of RPE65 activity have been developed and identified. Physiological roles of RPE65 in the retina have been clarified through use of pharmacological modulators. Knowledge of disease-causing RPE65 mutations and their pathogenic mechanisms has advanced.