Analysis of the blind Drosophila mutant ninaB identifies the gene encoding the key enzyme for vitamin A formation invivo

Lintig, Johannes von; Dreher, Armin; Kiefer, Cornelia; Wernet, Mathias F.; Vogt, Klaus

doi:10.1073/pnas.031576398

Cited by 80 publications

(58 citation statements)

References 28 publications

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“…In summary, our findings provide a functional link between vertebrate RPE65 and insect NinaB, which are both essential for the synthesis of the visual chromophore (3,13). The double function of NinaB supports the conclusion that RPE65 is a retinoid isomerase, as it is plausible that members of a family have retained a potential that already had emerged in an ancestor.…”

Section: Discussionsupporting

confidence: 74%

“…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)(5)(6)(7).…”

Section: Rpe65 ͉ Vision ͉ Visual Chromophorementioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 74%

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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“…VP14 also belongs to a more broadly defined family of CCDs present in bacteria, plants, and animals (von Lintig and Vogt, 2004). These enzymes range from the apocarotenoid-15,15'-oxygenase of Synechocystis spp to the human b-carotene 15,15'-monooxygenase, the enzyme responsible for the production of retinol (vitamin A) (von Lintig and Vogt, 2000;von Lintig et al, 2001). …”

Section: Vp14 As the Prototypementioning

confidence: 99%

Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid

et al. 2010

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The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-Å resolution, provides both insight into the determinants of regio-and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

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“…65 The chromophore of rhodopsin in the fly, 11-cis 3-hydroxyretinal, is derived from vitamin A of the diet. Vitamin A is taken up and processed to 11-cis retinal through multiple biochemical reactions, which are catalyzed by the gene products of ninaB, 66 suggesting defects associated with the ER accumulation of the non-productive Rh1 dimers containing both wild-type and mutant Rh1. Consistently, retinal degeneration is more severe in NinaE heterozygotes than in homozygotes, 78 supporting the notion that the non-productive Rh1 dimers are more stable and exert a more profound effect than those containing only mutant Rh1.…”

Section: Biosynthesis Of Rh1 Rhodopsin: Opsin and The Retinal Chromopmentioning

confidence: 99%

Molecular genetics of retinal degeneration: A Drosophila perspective

Shieh

2011

fly

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Analysis of the blind Drosophila mutant ninaB identifies the gene encoding the key enzyme for vitamin A formation invivo

Cited by 80 publications

References 28 publications

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

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

Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid

Molecular genetics of retinal degeneration: A Drosophila perspective

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