Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function

Kiser, Philip D.; Zhang, Jianye; Sharma, Aditya; Angueyra, Juan; Kolesnikov, Alexander V.; Badiee, Mohsen; Tochtrop, Gregory P.; Kinoshita, Junzo; Peachey, Neal S.; Li, Wei; Kefalov, Vladimir J.; Palczewski, Krzysztof

doi:10.1085/jgp.201711815

Cited by 29 publications

(42 citation statements)

References 93 publications

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“…Pharmacological RPE65 inhibition significantly reduces 11cRAL levels in multiple models e.g. by Ret-NH 2 in zebrafish (20), by emixustat in mice (26) and by emixustat or fenretinide in ex vivo RPE microsomes (32). Here as expected, dark-adapted, wildtype larvae treated with emixustat display a ~10-fold reduction in 11cRAL.…”

Section: Differential Requirements Of Rpe65 For Immediate and Early Csupporting

confidence: 59%

“…We exploited emixustat for its chemical ability to scavenge retinal and inhibit the RPE65 isomerase (26). Likewise, fenretinide causes depletion of vitamin A by disrupting the retinoldependent binding of RBP4 to transthyretin (35), and also inhibits the DES1 isomerase (31)(32)(33). A1120 is a more-selective RBP4 antagonist.…”

Section: Discussionmentioning

confidence: 99%

“…electrophysiology) as the primary endpoint. Reduced cone photosensitivity was observed in live mice and isolated retinas treated with visual cycle inhibitors (32). To our knowledge, no previous studies investigated the relationship between visual cycle modulation and cone photopic vision.…”

Section: Visual Cycle Modulationmentioning

confidence: 92%

“…Following 9cRAL treatment, light sensitivity is restored long-term in Rpe65 -/mice with attenuated accumulation of atREs (30). Fenretinide (4-HPR), a derivative of retinoic acid is reported to inhibit DES1 without affecting RPE65 activity (31)(32)(33). Fenretinide also competes with retinol for binding to retinol-binding protein (RBP4) in blood, causing a mild vitamin A deficiency (34).…”

Section: Visual Cycle Modulationmentioning

confidence: 99%

“…Previous studies demonstrate 5 dpf zebrafish rely exclusively on cones for vision (38). Emixustat is a potent RPE65 inhibitor; while targets of fenretinide include DES1 (the putative isomerase II) (32) and retinol-binding protein 4 (Rbp4) in blood (34). Larvae were raised under normal cyclic light conditions (14 h light, 10 h dark) for the duration of the experiment and treated with emixustat or fenretinide from 3 dpf.…”

Section: Fenretinide But Not Emixustat Impairs Late Cone Photopic Vmentioning

confidence: 99%

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Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision

Ward

Kaylor

Cobice³

et al. 2020

Preprint

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Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under

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Section: Differential Requirements Of Rpe65 For Immediate and Early Csupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Visual Cycle Modulationmentioning

confidence: 92%

Section: Visual Cycle Modulationmentioning

confidence: 99%

Section: Fenretinide But Not Emixustat Impairs Late Cone Photopic Vmentioning

confidence: 99%

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Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision

Ward

Kaylor

Cobice³

et al. 2020

Preprint

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Alkene‐Cleaving Carotenoid Cleavage Dioxygenases

Kiser

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Carotenoid cleavage dioxygenases (CCDs) constitute a family of enzymes that catalyze reactions of carotenoids, stilbenoids, and closely related compounds with dioxygen to achieve regioselective oxidative splitting of their alkene bonds into carbonyl‐containing products. This activity is enabled by a nonheme iron cofactor found in all such enzymes that facilitates activation of dioxygen for the reaction. These enzymes coordinate iron using four primary sphere His residues and an associated set of three outer sphere Glu residues. In their resting states, the iron centers of these enzymes are in a high‐spin ( S = 2) Fe II electronic configuration and contain a bound solvent molecule making them five coordinate with a distorted square pyramidal geometry. The CCD iron center is reactive toward nitric oxide in the presence or absence of organic substrate and the resulting S = 3/2 {FeNO} 7 complex, which mimics in some respects an iron‐oxy adduct, has been used to study substrate binding to the CCD active site. Crystallographic studies using cobalt‐substituted CCDs have enabled structures of these enzymes in complex with stilbenoid substrates to be determined revealing the positioning of the scissile alkene bond with respect to the metal center. CCDs adopt a seven‐bladed β‐propeller fold with iron coordinated on the top end of the propeller axis where it is covered by an α‐helical dome that constitutes a bulk of the active site structure. While the modes of iron coordination and overall structure of carotenoid‐ and stilbenoid‐cleaving CCDs are similar, these enzymes are divergent with respect to the structure of their substrate‐binding clefts and membrane‐binding characteristics. CCDs are broadly distributed in nature and play important roles in diverse and numerous biologic processes ranging from production of retinal chromophores for light detection to degradation of lignin‐derived stilbenes in pulping‐waste sludge.

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Aberrant RNA splicing is the major pathogenic effect in a knock‐in mouse model of the dominantly inherited c.1430A>G humanRPE65mutation

Furhang

Ray

et al. 2019

Human Mutation

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Human RPE65 mutations cause a spectrum of retinal dystrophies that result in blindness. While RPE65 mutations have been almost invariably recessively inherited, a c.1430A>G (p.(D477G)) mutation has been reported to cause autosomal dominant retinitis pigmentosa (adRP). To study the pathogenesis of this human mutation, we have replicated the mutation in a knock‐in (KI) mouse model using CRISPR/Cas9‐mediated genome editing. Significantly, in contrast to human patients, heterozygous KI mice do not exhibit any phenotypes in visual function tests. When raised in regular vivarium conditions, homozygous KI mice display relatively undisturbed visual functions with minimal retinal structural changes. However, KI/KI mouse retinae are more sensitive to light exposure and exhibit signs of degenerative features when subjected to light stress. We find that instead of merely producing a missense mutant protein, the A>G nucleotide substitution greatly affects appropriate splicing of Rpe65 mRNA by generating an ectopic splice site in comparable context to the canonical one, thereby disrupting RPE65 protein expression. Similar splicing defects were also confirmed for the human RPE65 c.1430G mutant in an in vitro Exontrap assay. Our data demonstrate that a splicing defect is associated with c.1430G pathogenesis, and therefore provide insights in the therapeutic strategy for human patients.

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Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function

Cited by 29 publications

References 93 publications

Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision

Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision

Alkene‐Cleaving Carotenoid Cleavage Dioxygenases

Aberrant RNA splicing is the major pathogenic effect in a knock‐in mouse model of the dominantly inherited c.1430A>G humanRPE65mutation

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