Synthesis of 11‐cis‐locked bicyclo[5.1.0]octanyl retinal and an enantioselective binding to bovine opsin

Fujimoto, Yukari; Xie, Rongyuan; Tully, Sarah E.; Berova, Nina; Nakanishi, Koji

doi:10.1002/chir.10076

Cited by 9 publications

(12 citation statements)

References 18 publications

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“…Synthesis of 11-cis-7-Ring Retinals-Synthesis of 11-cis-7-ring retinals was performed as described previously with some modifications (17)(18)(19). All of the reactions were performed in a dried nitrogen atmosphere unless otherwise specified.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

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Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration.

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Section: Methodsmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

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“…Synthesis of 11-cis-7-Ring-retinals-11-cis-7-ring-retinals were synthesized according to published procedures (12,28,29).…”

Section: Methodsmentioning

confidence: 99%

Biochemical and Physiological Properties of Rhodopsin Regenerated with 11-cis-6-Ring- and 7-Ring-retinals

Kuksa¹,

Bartl

Maeda³

et al. 2002

Journal of Biological Chemistry

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Phototransduction is initiated by the photoisomerization of rhodopsin (Rho) chromophore 11-cis-retinylidene to all-trans-retinylidene. Here, using Rho regenerated with retinal analogs with different ring sizes, which prevent isomerization around the C 11 ‫؍‬C 12 double bond, the activation mechanism of this G-protein-coupled receptor was investigated. We demonstrate that 11-cis-7-ring-Rho does not activate G-protein in vivo and in vitro, and that it does not isomerize along other double bonds, suggesting that it fits tightly into the binding site of opsin. In contrast, bleaching 11-cis-6-ring-Rho modestly activates phototransduction in vivo and at low pH in vitro. These results reveal that partial activation is caused by isomerization along other double bonds in more rigid 6-locked retinal isomers and protonation of key residues by lowering pH in 11-cis-6-ring-Rhos. Full activation is not achieved, because isomerization does not induce a complete set of conformational rearrangements of Rho. These results with 6-and 7-ringconstrained retinoids provide new insights into Rho activation and suggest a potential use of locked retinals, particularly 11-cis-7-ring-retinal, to inactivate opsin in some retinal degeneration diseases.In vertebrate retinal photoreceptor cells, isomerization of the visual pigment chromophore, 11-cis-retinal to all-trans-retinal, triggers a set of reactions collectively termed the phototransduction cascade (1, 2). The phototransduction events are initiated by activated rhodopsin (Rho*) 1 and progress through a classical G-protein cascade, ultimately leading to neuronal signaling. Metarhodopsin II (or Meta II, Rho*), the catalytically active intermediate generated by photoisomerization of Rho chromophore, contains all-trans-retinal covalently bound to Lys 296 of opsin via the deprotonated Schiff base. Subsequently, Meta II undergoes reprotonation, and the photolyzed chromophore is hydrolyzed and released from opsin (3-5). The precise mechanism of Rho activation by the photoisomerized chromophore is unknown (6).The photobleaching process of rhodopsin has been investigated using retinal analogs that contained an extra ring between C 10 and C 13 , making retinal non-isomerizable around the 11-cis double bond (7-12). An artificial visual pigment with restricted C 9 -C 11 motion forms normal photolysis intermediates (13), suggesting an importance of C 11 ϭC 12 bond isomerization in the activation of Rho. More recently, it was reported that after photoisomerization, the ␤-ionone ring of the chromophore moves to a new position during the transition to Meta II (7). Jang et al. (14) showed using 6-ring-constrained retinal isomers and the crystal structure of Rho in the ground state (15) that if this movement is restricted, only residual activity could be observed. Locked retinal analogs were also used to study visual transduction in vivo using vitamin A-deprived rats (16, 17). These animals had approximately half of the normal complement of rhodopsin, and injection of locked retinal led to the appearan...

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“…It stems from our earlier work conducted on the sevenmembered ring unit 3, synthesized from 2-cyclohepten-1-one in five steps (14). The hydroxylated β-ionone ring structure can be introduced by employing a Wittig reaction between aldehyde 3 and synthon 2, the latter being prepared from dehydro-β-cyclocitral (also known as safranal) in seven steps as outlined in Scheme 2.…”

Section: Resultsmentioning

confidence: 99%

“…The Horner-WadsworthEmmons (HWE) reaction can be used to install a nitrile group at the C-14 position with reagent 4, followed by its reduction to the corresponding aldehyde, which would be subjected to further reduction to the corresponding primary alcohol onto which a bromoester can be esterified in the final stages. Synthon 3 has been prepared from the commercially available 2-cyclohepten-1-one, according to our earlier report (14). The synthesis featured an allylic oxidation of 2-cyclohepten-1-one, a three-carbon homologation by HWE reaction with the reagent bearing the nitrile functionality, and lastly, a partial reduction of the nitrile to the corresponding aldehyde.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of an 11-cis-locked biotinylated retinoid for sequestering 11-cis-retinoid binding proteins

Matsuda¹,

Zhang²,

Holmes³

et al. 2006

Can. J. Chem.

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The synthesis of a seven-membered ring locked analogue of 11-cis-retinol, tethered to a cross-linking moiety on C-15 and a lysine-extended biotin on the C-3, was accomplished for its utilization as a probe to fish out retinol binding proteins that may be involved in the reisomerization of retinal from all-trans to 11-cis in the visual cycle.Résumé : La synthèse d'un analogue de 11-cis-rétinol sous la forme d'un anneau verrouillé, comportant sept membres, attachés en partie, au C-15, avec un groupe ayant la possibilité de se liér aux protéines a été réalisée. En plus, l'analogue est attaché de l'autre côté sur le C-3, avec une lysine biotine étendue. Cette synthèse a été réalisée afin d'utilizer le composé comme agent détecteur des protéines qui portent des rétinols et qui pourraient être impliquées dans la réisomerization du all-trans retinal au 11-cis dans le cycle de vision.

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Synthesis of 11‐cis‐locked bicyclo[5.1.0]octanyl retinal and an enantioselective binding to bovine opsin

Cited by 9 publications

References 18 publications

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Biochemical and Physiological Properties of Rhodopsin Regenerated with 11-cis-6-Ring- and 7-Ring-retinals

Synthesis of an 11-cis-locked biotinylated retinoid for sequestering 11-cis-retinoid binding proteins

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