Cloning and Characterization of a Human β,β-Carotene-15, 15′-Dioxygenase That Is Highly Expressed in the Retinal Pigment Epithelium

Yan, Weiming; Jang, Geeng Fu; Haeseleer, Françoise; Esumi, Noriko; Chang, Jinghua Tsai; Kerrigan, Michelle; Campochiaro, Michael; Campochiaro, Peter A.; Palczewski, Krzysztof; Zack, Donald J.

doi:10.1006/geno.2000.6476

Cited by 148 publications

(117 citation statements)

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“…The requirement of ␤-carotene as the C 40 carotenoid acted on by the NinaB BCO is suggested by the observation that bacterially expressed NinaB BCO does not process zeaxanthin or other hydroxylated C 40 carotenoids to the C 20 3-OH retinal (26). Similar specificity was observed for mammalian BCO homologs (12,13). If Drosophila in vivo conditions of NinaB BCO activity are the same, the successful use of zeaxanthin or lutein (16) as a dietary source for the 3-OH retinal requires that these hydroxylated C 40 carotenoids are first converted to ␤-carotene.…”

Section: Discussionmentioning

confidence: 82%

“…The availability of vitamin A for metabolic processes is governed by multiple factors, including dietary absorption, transport, metabolism, and storage (11). A human BCO is expressed in the retinal pigment epithelium and also in the kidney, intestine, liver, brain, stomach, and testis (12,13), suggesting that the processing of dietary carotenoids occurs in a variety of vertebrate tissues. Additional studies show that centric cleavage of ␤-carotene plays a major role in the processing of carotenoids (14,15).…”

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confidence: 99%

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Drosophila NinaB and NinaD Act Outside of Retina to Produce Rhodopsin Chromophore

Gu¹,

Yang²,

Mitchell

et al. 2004

Journal of Biological Chemistry

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The Drosophila ninaB gene encodes a ␤,␤-carotene-15,15 -oxygenase responsible for the centric cleavage of ␤-carotene that produces the retinal chromophore of rhodopsin. The ninaD gene encodes a membrane receptor required for efficient use of ␤-carotene. Despite their importance to the synthesis of visual pigment, we show that these genes are not active in the retina. Mosaic analysis shows that ninaB and ninaD are not required in the retina, and exclusive retinal expression of either gene, or both genes simultaneously, does not support rhodopsin biogenesis. In contrast, neuron-specific expression of ninaB and ninaD allows for rhodopsin biogenesis. Additional directed expression studies failed to identify other tissues supporting ninaB activity in rhodopsin biogenesis. These results show that nonretinal sites of NinaB ␤,␤-carotene-15,15 -oxygenase activity, likely neurons of the central nervous system, are essential for production of the visual chromophore. Retinal or another C 20 retinoid, not members of the ␤-carotene family of C 40 carotenoids, are supplied to photoreceptors for rhodopsin biogenesis.Mutants in eight Drosophila genes, designated ninaA through ninaH, are characterized by reduced rhodopsin levels in photoreceptors and altered electroretinograms (1). The opsin protein component of rhodopsin is coded by the ninaE gene (2, 3). The low rhodopsin phenotypes observed in other nina mutants are caused by deficits in the post-translational rhodopsin maturation process. For example, ninaA encodes a molecular chaperone required for movement of newly synthesized rhodopsin from the endoplasmic reticulum to the photosensitive rhabdomeric membranes (4, 5). In the case of ninaB and ninaD, defective rhodopsin production is the result of a failure to generate the chromophore of rhodopsin, 3-OH retinal (6).Animal species usually obtain retinals in their food. Plants and microorganisms produce C 40 carotenoids such as ␤-carotene and zeaxanthin, which animals metabolize to C 20 retinoids. In Drosophila, the ninaD gene encodes a membrane "scavenger" receptor proposed to mediate the cellular uptake of carotenoids (7). The ninaB gene encodes a ␤,␤-carotene-15,15Ј-oxygenase (BCO) 1 responsible for the centric cleavage of ␤-carotene to form retinal (8). This enzyme was originally named as a ␤-carotene dioxygenase. It has now been renamed BCO (9) in light of recent data showing related enzymes act as monooxygenases (10).In vertebrates, vitamin A is essential for development and differentiation processes as well as its role in vision. The availability of vitamin A for metabolic processes is governed by multiple factors, including dietary absorption, transport, metabolism, and storage (11). A human BCO is expressed in the retinal pigment epithelium and also in the kidney, intestine, liver, brain, stomach, and testis (12, 13), suggesting that the processing of dietary carotenoids occurs in a variety of vertebrate tissues. Additional studies show that centric cleavage of ␤-carotene plays a major role in the processing of carote...

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Drosophila NinaB and NinaD Act Outside of Retina to Produce Rhodopsin Chromophore

Gu¹,

Yang²,

Mitchell

et al. 2004

Journal of Biological Chemistry

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“…Thereafter, several related carotenoid-15,15Ј-oxygenases (CMO1) have been identified and characterized in vertebrates including human beings (4)(5)(6)(7). In addition, in vertebrates a second type of carotenoid-oxygenase, carotenoid-9Ј,10Ј-monooxygenase (CMO2) has been identified that cleaves carotenoids asymmetrically (8,9), although its physiological function is not yet fully understood.…”

Section: Rpe65 ͉ Vision ͉ Visual Chromophorementioning

confidence: 99%

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide

Oberhauser

Voolstra

Bangert

et al. 2008

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

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In animals, successful production of the visual chromophore (11-cis-retinal or derivatives thereof such as 11-cis-3-hydroxy-retinal) is essential for photoreceptor cell function and survival. These carotenoid-derived compounds must combine with a protein moiety (the opsin) to establish functional visual pigments. Evidence from cell culture systems has implicated that the retinal pigment epithelium protein of 65 kDa (RPE65) is the long-sought all-trans to 11-cis retinoid isomerase. RPE65 is structurally related to nonheme iron oxygenases that catalyze the conversion of carotenoids into retinoids. In vertebrate genomes, two carotenoid oxygenases and RPE65 are encoded, whereas in insect genomes only a single representative of this protein family, named NinaB (denoting neither inactivation nor afterpotential mutant B), is encoded. We here cloned and functionally characterized the ninaB gene from the great wax moth Galleria mellonella. We show that the recombinant purified enzyme combines isomerase and oxygenase (isomerooxygenase) activity in a single polypeptide. From kinetics and isomeric composition of cleavage products of asymmetrical carotenoid substrates, we propose a model for the spatial arrangement between substrate and enzyme. In Drosophila, we show that carotenoid-isomerooxygenase activity of NinaB is more generally found in insects, and we provide physiological evidence that carotenoids such as 11-cis-retinal can promote visual pigment biogenesis in the dark. Our study demonstrates that trans/cis isomerase activity can be intrinsic to this class of proteins and establishes these enzymes as key components for both invertebrate and vertebrate vision. RPE65 ͉ vision ͉ visual chromophoreA nimal visual pigments (rhodopsins) are bipartite G-proteincoupled receptors consisting of an opsin moiety and a carotenoid-derived retinylidene chromophore (1). Two fundamental issues in the pathway for visual chromophore production have resisted molecular analysis for a long time: first, the oxidative cleavage of C 40 carotenoids into C 20 retinoids; and second, the all-trans to 11-cis isomerization of retinoids.The molecular basis for the oxidative cleavage was resolved by cloning and characterization of NinaB (denoting neither inactivation nor afterpotential mutant B), which converts carotenoids into retinoids in Drosophila melanogaster (2, 3). Thereafter, several related carotenoid-15,15Ј-oxygenases (CMO1) have been identified and characterized in vertebrates including human beings (4-7). In addition, in vertebrates a second type of carotenoid-oxygenase, carotenoid-9Ј,10Ј-monooxygenase (CMO2) has been identified that cleaves carotenoids asymmetrically (8, 9), although its physiological function is not yet fully understood.The isomerization problem concerns the questions of how the visual chromophore is produced to establish functional visual pigments and, in vertebrates, how the all-trans visual photoproduct is isomerized back to the 11-cis chromophore, to maintain visual responsiveness. Recently, evidence in cell cultur...

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“…Although beta-carotene cleavage activity was demonstrated in cell-free extracts derived from mammalian small intestine in the 1960s, purification of the enzyme proved surprisingly challenging [47][48][49][50]. It was not until the advent of molecular biological approaches and mass spectral sequencing that the beta-carotene cleavage enzyme was cloned first from Drosophila and chicken and later from humans [54][55][56][57][58]. It is a cytosolic enzyme primarily localized in the duodenal mucosa although it has been found in liver and in the eye.…”

Section: Carotenoid Metabolic Enzymesmentioning

confidence: 99%

Vertebrate and invertebrate carotenoid-binding proteins

Bhosale

Bernstein

2007

Archives of Biochemistry and Biophysics

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In invertebrates and vertebrates, carotenoids are ubiquitous colorants, antioxidants, and provitamin A compounds that must be absorbed from dietary sources and transported to target tissues where they are taken up and stabilized to perform their physiological functions. These processes occur in a specific and regulated manner mediated by high-affinity carotenoid-binding proteins. In this minireview, we examine the published literature on carotenoid-binding proteins in vertebrate and invertebrate systems, and we report our initial purification and characterization of a novel luteinbinding protein isolated from liver of Japanese quail (Coturnix japonica).

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Cloning and Characterization of a Human β,β-Carotene-15, 15′-Dioxygenase That Is Highly Expressed in the Retinal Pigment Epithelium

Cited by 148 publications

References 55 publications

Drosophila NinaB and NinaD Act Outside of Retina to Produce Rhodopsin Chromophore

Drosophila NinaB and NinaD Act Outside of Retina to Produce Rhodopsin Chromophore

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide

Vertebrate and invertebrate carotenoid-binding proteins

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