Rod Outer Segment Retinol Dehydrogenase: Substrate Specificity and Role in Phototransduction

Palczewski, Krzysztof; Jäger, Stefan; Buczyłko, Janina; Crouch, Rosalie K.; Bredberg, D L; Hofmann, Klaus; Asson-Batres, Mary Ann; Saari, John C.

doi:10.1021/bi00250a027

Cited by 174 publications

(142 citation statements)

References 61 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…Although ABCA4 can flip N-11-cis-retinylidene-PE from the luminal to the cytoplasmic leaflet of disk membranes, this function alone cannot efficiently remove excess 11-cis-retinal from disk membranes because 11-cis-retinal is a poor substrate for retinol dehydrogenase (RDH) 8, the only known retinol dehydrogenase in photoreceptor disk membranes (16,17). However, the 11-cis isomer of N-retinylidene-PE has been previously reported to undergo chemical isomerization in the dark, although the physiological significance of this reaction has been unclear (18).…”

Section: Abca4mentioning

confidence: 99%

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Quazi

Molday

2014

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

110

101

View full text Add to dashboard Cite

The visual cycle is a series of enzyme-catalyzed reactions which converts all-trans-retinal to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells. Although essential for vision, 11-cis-retinal like all-trans-retinal is highly toxic due to its highly reactive aldehyde group and has to be detoxified by either reduction to retinol or sequestration within retinal-binding proteins. Previous studies have focused on the role of the ATP-binding cassette transporter ABCA4 associated with Stargardt macular degeneration and retinol dehydrogenases (RDH) in the clearance of all-trans-retinal from photoreceptors following photoexcitation. How rod and cone cells prevent the accumulation of 11-cis-retinal in photoreceptor disk membranes in excess of what is required for visual pigment regeneration is not known. Here we show that ABCA4 can transport N-11-cis-retinylidene-phosphatidylethanolamine (PE), the Schiff-base conjugate of 11-cis-retinal and PE, from the lumen to the cytoplasmic leaflet of disk membranes. This transport function together with chemical isomerization to its all-trans isomer and reduction to all-trans-retinol by RDH can prevent the accumulation of excess 11-cis-retinal and its Schiff-base conjugate and the formation of toxic bisretinoid compounds as found in ABCA4-deficient mice and individuals with Stargardt macular degeneration. This segment of the visual cycle in which excess 11-cis-retinal is converted to all-transretinol provides a rationale for the unusually high content of PE and its long-chain unsaturated docosahexaenoyl group in photoreceptor membranes and adds insight into the molecular mechanisms responsible for Stargardt macular degeneration.T he visual cycle plays a crucial role in the removal of all-transretinal from photoreceptor cells following photoexcitation and its conversion to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells (1). Deficient clearance of all-trans-retinal and its Schiff-base conjugate N-retinylidenephosphatidylethanolamine (PE) from rod and cone photoreceptor outer segments results in condensation reactions which produce a mixture of bisretinoid products including the pyridinium bisretinoid compound A2PE and its hydrolytic product A2E (2, 3). These bisretinoid compounds accumulate as lipofuscin deposits in retinal pigment epithelial (RPE) cells upon phagocytosis of outer segments and have been implicated in the pathology of a number of retinal degenerative diseases. This is particularly evident in autosomal recessive Stargardt macular degeneration in which mutations in the ATP-binding cassette (ABC) transporter ABCA4 which impair the N-retinylidene-PE transport activity of ABCA4 cause a buildup of lipofuscin, atrophy of the central retina, and severe progressive loss in vision (4-8).In initial studies, Abca4 knockout mice were reported to show a light-dependent accumulation of all-trans-retinal, PE, and N-retinylidene-PE in photoreceptors and lipofuscin and A2E in RPE (9). This led to a model...

show abstract

Section: Abca4mentioning

confidence: 99%

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Quazi

Molday

2014

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

110

101

View full text Add to dashboard Cite

show abstract

“…pro-R and pro-S designations were used for 15-3 H-labeled retinols produced by the enzyme for which the stereospecificity is known (24). (24,28). RDH activities were measured using the phase partition assay (29) or HPLC assays as described (24).…”

Section: Preparation Of Anti-rdh11 -Rdh13 -Rdh14mentioning

confidence: 99%

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Haeseleer¹,

Jang²,

Imanishi³

et al. 2002

Journal of Biological Chemistry

Self Cite

184

227

View full text Add to dashboard Cite

Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11-14) that display dualsubstrate specificity, uniquely metabolizing all-trans-and cis-retinols with C 15 pro-R specificity. RDH11-14 could be involved in the first step of all-trans-and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dualsubstrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cisretinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.Retinoids are indispensable light-sensitive elements of vision and also serve as essential modulators of cellular differentiation and proliferation in diverse cell types, including those comprising the epithelium and immune system. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid receptors. All-trans-retinoic acid signals through specific interactions with the nuclear retinoic acid receptors, whereas its isomer, 9-cis-retinoic acid, is a high affinity ligand of retinoic acid receptors and retinoid X receptors. In the retina, light-dependent photoisomerization of 11-cis-retinylidene to the all-transretinylidene moiety of rod and cone photoreceptors is a key reaction that triggers visual * This research was supported by National Institutes of Health Grants EY08061, CA75173, and DK59125, a grant from Research to Prevent Blindness, Inc. (to the Department of Ophthalmology, University of Washington), and by the E. K. Bishop Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2 and Tables 1-3. § These authors contributed equally to this work. § § Recipient of a Research to Prevent Blindness Senior Investigator Award. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Seattle,; E-mail: palczews@u.washington.edu. Transformations of retinoids occur mostly through enzymatic or photochemical reactions, although they readily isomerize non-enzymatically to thermodynamic equilibriu...

show abstract

“…These results suggest that the soluble enzymes are not likely to be responsible for a significant contribution to 11-cis-retinol oxidation in the RPE cytosol. All-trans-RDH activity is detected in both 11-cis-rdhϩ/ϩ and 11-cis-rdhϪ/Ϫ RPE membranes in a pro-S- [4-3 H]NADPH-dependent manner, and are most likely a result of ROS contamination during the RPE microsomal preparations (18,63).…”

Section: Detected With Pro-s-[4-mentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Rod Outer Segment Retinol Dehydrogenase: Substrate Specificity and Role in Phototransduction

Cited by 174 publications

References 61 publications

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

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

Contact Info

Product

Resources

About