Inhibitors of retinyl ester formation also prevent the biosynthesis of 11-cis-retinol

Trehan, Achla; Cañada, F. Javier; Rando, Robert R.

doi:10.1021/bi00454a001

Cited by 67 publications

(78 citation statements)

References 12 publications

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“…This finding suggests that the order of incubation of inhibitors of RPE65 would be expected to be important to reveal effective inhibition. Preincubation of these membranes with vitamin A rapidly produces all-trans-retinyl esters through rapid esterification mediated by LRAT (2). The synthesized all-transretinyl esters are tightly bound to RPE65, and then processed .…”

Section: Resultsmentioning

confidence: 99%

“…LRAT catalyzes the esterification of vitamin A by using lecithin as the acyl donor to generate the all-trans-retinyl esters (1). LRAT is an essential component in the pathway because longchain all-trans-retinyl esters serve as substrates for the isomerization reaction (2)(3)(4)(5). The high degree of hydrophobicity of these esters requires the availability of a chaperone to mobilize and deliver them to the appropriate enzyme, in this case the IMH.…”

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confidence: 99%

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

Gollapalli

Rando

2004

Proc. Natl. Acad. Sci. U.S.A.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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

Gollapalli

Rando

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Rpe65 functions to extract insoluble atRE from the membrane and present them to IMH. IMH effects the conversion of atRE to 11cROL (1,3,48). Finally, 11cROL is oxidized to 11cRAL by 11cROL dehydrogenase (11cRDH) in ER membranes (49).…”

Section: Discussionmentioning

confidence: 99%

Rpe65 Is a Retinyl Ester Binding Protein That Presents Insoluble Substrate to the Isomerase in Retinal Pigment Epithelial Cells

Mata¹,

Moghrabi²,

Lee³

et al. 2004

Journal of Biological Chemistry

121

127

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Photon capture by a rhodopsin pigment molecule induces 11-cis to all-trans isomerization of its retinaldehyde chromophore. To restore light sensitivity, the alltrans-retinaldehyde must be chemically re-isomerized by an enzyme pathway called the visual cycle. Rpe65, an abundant protein in retinal pigment epithelial (RPE) cells and a homolog of ␤-carotene dioxygenase, appears to play a role in this pathway. Rpe65 ؊/؊ knockout mice massively accumulate all-trans-retinyl esters but lack 11-cis-retinoids and rhodopsin visual pigment in their retinas. Mutations in the human RPE65 gene cause a severe recessive blinding disease called Leber's congenital amaurosis. The function of Rpe65, however, is unknown. Here we show that Rpe65 specifically binds alltrans-retinyl palmitate but not 11-cis-retinyl palmitate by a spectral-shift assay, by co-elution during gel filtration, and by co-immunoprecipitation. Using a novel fluorescent resonance energy transfer (FRET) binding assay in liposomes, we demonstrate that Rpe65 extracts all-trans-retinyl esters from phospholipid membranes. Assays of isomerase activity reveal that Rpe65 strongly stimulates the enzymatic conversion of all-trans-retinyl palmitate to 11-cis-retinol in microsomes from bovine RPE cells. Moreover, we show that addition of Rpe65 to membranes from rpe65 ؊/؊ mice, which possess no detectable isomerase activity, restores isomerase activity to wild-type levels. Rpe65 by itself, however, has no intrinsic isomerase activity. These observations suggest that Rpe65 presents retinyl esters as substrate to the isomerase for synthesis of visual chromophore. This proposed function explains the phenotype in mice and humans lacking Rpe65.Light perception in vertebrates is mediated by a group of G protein-coupled receptors called the opsins. Most opsin pigments contain 11-cis-retinaldehyde (11cRAL) 1 as the light-absorbing chromophore. Absorption of a photon induces 11-cis to all-trans isomerization of the chromophore, resulting in the activated species, metarhodopsin II. After a brief period, metarhodopsin II decays to yield apo-rhodopsin and free alltrans-retinaldehyde (atRAL). Before light sensitivity of the pigment can be restored, the atRAL must be chemically re-isomerized to 11cRAL by a metabolic pathway called the visual cycle. Most steps in this pathway take place within cells of the retinal pigment epithelium (RPE) adjacent to the photoreceptors. The key step in this pathway is all-trans to 11-cis re-isomerization of the retinoid, which is catalyzed by an enzyme activity called isomerohydrolase (IMH). IMH has been shown to use fatty acyl esters of retinol as a substrate (1, 2), harnessing the energy of ester hydrolysis [⌬G ϭ Ϫ5 kcal/mol (3)] for the endothermic conversion of all-trans-retinol (atROL) to 11-cis-retinol (11cROL) (ϩ4.1 kcal/mol, Ref. 4). IMH has never been purified or cloned. Leber's congenital amaurosis (LCA) is a severe and relatively common autosomal recessive disease that results in blindness at birth. LCA is frequently caused by mutations in the RP...

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“…Therefore, it is possible that 13-cis-retinol observed in the previous studies was a result of hydrolysis of the esters during the processing of these samples. Lack of accumulation of cis-retinols could be explained by low affinity of retinoid-binding proteins to retinols as compared with aldehydes (40) and powerful lecithin:retinol acyl transferase activity in RPE (35,37,41). After bleaching, there is a ϳ30% elevation of cis-retinols (Fig.…”

Section: Accumulation Of 11-cis-retinyl Esters In 11-cis-rdhϫ/ϫmentioning

confidence: 99%

Characterization of a Dehydrogenase Activity Responsible for Oxidation of 11-cis-Retinol in the Retinal Pigment Epithelium of Mice with a Disrupted RDH5 Gene

Jang

Hooser

Kuksa

et al. 2001

Journal of Biological Chemistry

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In the vertebrate retina, the final step of visual chromophore production is the oxidation of 11-cis-retinol to 11-cis-retinal. This reaction is catalyzed by 11-cis-retinol dehydrogenases (11-cis-RDHs), prior to the chromophore rejoining with the visual pigment apo-proteins. The RDH5 gene encodes a dehydrogenase that is responsible for the majority of RDH activity. In humans, mutations in this gene are associated with fundus albipunctatus, a disease expressed by delayed dark adaptation of both cones and rods. In this report, an animal model for this disease, 11-cis-rdh؊/؊ mice, was used to investigate the flow of retinoids after a bleach, and microsomal membranes from the retinal pigment epithelium of these mice were employed to characterize remaining enzymatic activities oxidizing 11-cis-retinol. Lack of 11-cis-RDH leads to an accumulation of cis-retinoids, particularly 13-cis-isomers. The analysis of 11-cisrdh؊/؊ mice showed that the RDH(s) responsible for the production of 11-cis-retinal displays NADP-dependent specificity toward 9-cis-and 11-cis-retinal but not 13-cisretinal. The lack of 13-cis-RDH activity could be a reason why 13-cis-isomers accumulate in the retinal pigment epithelium of 11-cis-rdh؊/؊ mice. Furthermore, our results provide detailed characterization of a mouse model for the human disease fundus albipunctatus and emphasize the importance of 11-cis-RDH in keeping the balance between different components of the retinoid cycle.

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Inhibitors of retinyl ester formation also prevent the biosynthesis of 11-cis-retinol

Cited by 67 publications

References 12 publications

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

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

Rpe65 Is a Retinyl Ester Binding Protein That Presents Insoluble Substrate to the Isomerase in Retinal Pigment Epithelial Cells

Characterization of a Dehydrogenase Activity Responsible for Oxidation of 11-cis-Retinol in the Retinal Pigment Epithelium of Mice with a Disrupted RDH5 Gene

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