Structural and biological aspects of carotenoid cleavage

Kloer, Daniel P.; Schulz, Georg E.

doi:10.1007/s00018-006-6176-6

Cited by 176 publications

(158 citation statements)

References 70 publications

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“…From an evolutionary standpoint, it might be expected that the RPE65 catalytic mechanism would resemble that of the carotenoid oxygenases (33,34). Mechanisms that involve participation of molecular oxygen in the isomerization reaction cannot be definitively ruled out, but would require especially complex chemistry that is not justified by the experimental evidence available to date.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of native RPE65, the retinoid isomerase of the visual cycle

Kiser

Golczak²,

Lodowski³

et al. 2009

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

141

227

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Vertebrate vision is maintained by the retinoid (visual) cycle, a complex enzymatic pathway that operates in the retina to regenerate the visual chromophore, 11-cis-retinal. A key enzyme in this pathway is the microsomal membrane protein RPE65. This enzyme catalyzes the conversion of all-trans-retinyl esters to 11-cis-retinol in the retinal pigment epithelium (RPE). Mutations in RPE65 are known to be responsible for a subset of cases of the most common form of childhood blindness, Leber congenital amaurosis (LCA). Although retinoid isomerase activity has been attributed to RPE65, its catalytic mechanism remains a matter of debate. Also, the manner in which RPE65 binds to membranes and extracts retinoid substrates is unclear. To gain insight into these questions, we determined the crystal structure of native bovine RPE65 at 2.14-Å resolution. The structural, biophysical, and biochemical data presented here provide the framework needed for an in-depth understanding of the mechanism of catalytic isomerization and membrane association, in addition to the role mutations that cause LCA have in disrupting protein function.isomerization ͉ metalloprotein ͉ monotopic membrane protein V ision begins when the 11-cis-retinylidene chromophore of rhodopsin is photoisomerized to all-trans-retinylidene, a process resulting in receptor activation and transduction of the light signal (1). After rhodopsin is photoactivated, it is no longer responsive to light, so for vision to continue, a trans-to-cis isomerization mechanism must be present to regenerate lightsensitive visual pigments. In vertebrates, after photoisomerization, all-trans-retinylidene is hydrolyzed from rhodopsin, reduced to all-trans-retinol, and transported to a tissue adjacent to the photoreceptor layer known as the retinal pigment epithelium (RPE), where enzymatic isomerization occurs (2). An RPEspecific, microsomal membrane protein with an apparent molecular mass of 65 kDa, known as RPE65, was determined to be responsible for trans-to-cis retinoid isomerase activity in the RPE (3-5). The importance of this protein in visual function is also evident from the observation that certain RPE65 mutations cause a form of the hereditary childhood blinding disease known as Leber congenital amaurosis (LCA) or the less severe, lateronset disease, retinitis pigmentosa (RP) (6-8).Based on sequence homology, RPE65 belongs to a family of carotenoid cleavage oxygenase (CCO) enzymes that oxidatively cleave ␤-carotene or apocarotenoids (9-11). However, RPE65 is distinct from all other members of this family in that it simultaneously cleaves and isomerizes all-trans-retinyl esters to 11-cisretinol and a fatty acid rather than oxidatively cleaving carotenoids (3-5, 11, 12). Unlike the reactions catalyzed by other CCO family members, there is no obvious role for molecular oxygen in RPE65 enzymology. The only family member with a known crystal structure is an apocarotenoid oxygenase from Synechocystis that is 25% identical and 42% homologous to human RPE65 (13). All members of this fa...

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Section: Resultsmentioning

confidence: 99%

Crystal structure of native RPE65, the retinoid isomerase of the visual cycle

Kiser

Golczak²,

Lodowski³

et al. 2009

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

141

227

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“…The SynACO enzyme is able to convert β-apo-carotenals and related molecules of various chain-lengths into retinal in vitro (59). However, the most common precursor of retinal, β-carotene appears not to be accepted by SynACO as its substrate in vitro (59)(60)(61), which is probably due to the selectivity of the enzyme's substrate binding site (61,62). It is not known whether or not the enzyme actually can produce retinal in vivo.…”

Section: Retinal Synthesis In Synechocystismentioning

confidence: 99%

Expression of holo-proteorhodopsin in Synechocystis sp. PCC 6803

Chen

Steen

Dekker

et al. 2016

Metabolic Engineering

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Retinal-based photosynthesis may contribute to the free energy conversion needed for growth of an organism carrying out oxygenic photosynthesis, like a cyanobacterium. After optimization, this may even enhance the overall efficiency of phototrophic growth of such organisms in sustainability applications. As a first step towards this, we here report on functional expression of the archetype proteorhodopsin in Synechocystis sp. PCC 6803. Upon use of the moderate-strength psbA2 promoter, holo-proteorhodopsin is expressed in this cyanobacterium, at a level of up to 10 5 molecules per cell, presumably in a hexameric quaternary structure, and with approximately equal distribution (on a protein-content basis) over the thylakoid and the cytoplasmic membrane fraction. These results also demonstrate that Synechocystis sp. PCC 6803 has the capacity to synthesize alltrans-retinal. Expressing a substantial amount of a heterologous opsin membrane protein causes a substantial growth retardation Synechocystis, as is clear from a strain expressing PROPS, a nonpumping mutant derivative of proteorhodopsin. Relative to this latter strain, proteorhodopsin expression, however, measurably stimulates its growth.

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“…Since their initial discovery in bacteria and plants, tremendous progress has been made in elucidating the biological substrates of these enzymes (1)(2)(3). Most characterized CCOs catalyze the oxidative cleavage of carotenoid carbon-carbon double bonds to yield aldehyde and/or ketone-containing apocarotenoid products (Fig.…”

Section: O 2 Revealed An Unambiguous Dioxygenase Pattern Of O 2 Incormentioning

confidence: 99%

Utilization of Dioxygen by Carotenoid Cleavage Oxygenases

Sui

Golczak

Zhang

et al. 2015

Journal of Biological Chemistry

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, previously reported to be a monooxygenase, using a purified enzyme sample revealed that it too is a dioxygenase. We also demonstrated that bovine RPE65 is not dependent on O 2 for its cleavage/isomerase activity. In conjunction with prior research, the results of this study resolve key issues regarding the utilization of O 2 by CCOs and indicate that dioxygenase activity is a feature common among double bondcleaving CCOs.

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Structural and biological aspects of carotenoid cleavage

Cited by 176 publications

References 70 publications

Crystal structure of native RPE65, the retinoid isomerase of the visual cycle

Crystal structure of native RPE65, the retinoid isomerase of the visual cycle

Expression of holo-proteorhodopsin in Synechocystis sp. PCC 6803

Utilization of Dioxygen by Carotenoid Cleavage Oxygenases

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