Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases:  Formation and Storage of Retinyl Esters

Maeda, Akiko; Maeda, Tadao; Imanishi, Yoshikazu; Golczak, Marcin; Moise, Alexander R.; Palczewski, Krzysztof

doi:10.1021/bi052382x

Cited by 34 publications

(35 citation statements)

References 48 publications

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“…Extensive studies in animals, including rats as well as WT and Abca4 −/− Rdh8 −/− double-KO mice that closely mimic many features of human retinal degeneration, showed that Ret-NH 2 exhibits a protective effect against lightinduced damage by preventing buildup of atRAL and its condensation products (7,33,50,51). But, Ret-NH 2 is (a) used as a substrate by LRAT, (b) a less potent inhibitor of RPE65 than emixustat, and (c) metabolized to retinol in vivo (7,26,33,35,39,50,(52)(53)(54). First, Ret-NH 2 is retained in the eye by the action of LRAT that produces its amidated precursor, and then the resulting retinyl amide is slowly hydrolyzed to evoke a long-lasting suppression of retinoid isomerase activity (35).…”

Section: Discussionmentioning

confidence: 99%

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

Zhang

Kiser²,

Badiee

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

Zhang

Kiser²,

Badiee

et al. 2015

J. Clin. Invest.

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“…Nuclei are stained with Hoechst 33342 (blue). (Golczak et al, 2005a,b;Maeda et al, 2006), with a prolonged mode of action because of its reversible amidation. Thus, the suppression of the visual function depends on the level of the accumulated amides of Ret-NH 2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effects of Potent Inhibitors of the Retinoid Cycle on Visual Function and Photoreceptor Protection from Light Damage in Mice

Maeda¹,

Maeda²,

Golczak³

et al. 2006

Mol Pharmacol

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Regeneration of the chromophore 11-cis-retinal is essential for the generation of light-sensitive visual pigments in the vertebrate retina. A deficiency in 11-cis-retinal production leads to congenital blindness in humans; however, a buildup of the photoisomerized chromophore can also be detrimental. Such is the case when the photoisomerized all-trans-retinal is produced but cannot be efficiently cleared from the internal membrane of the outer segment discs. Sustained increase of alltrans-retinal can lead to the formation of toxic condensation products in the eye. Thus, there is a need for potent, selective inhibitors that can regulate the flux of retinoids through the metabolism pathway termed the visual (retinoid) cycle. Here we systematically study the effects of the most potent inhibitor of this cycle, retinylamine (Ret-NH 2 ), on visual function in mice. Prolonged, sustainable, but reversible suppression of the visual function was observed by Ret-NH 2 as a result of its storage in a prodrug form, N-retinylamides. Direct comparison of other inhibitors such as fenretinide and 13-cis-retinoic acid showed multiple advantages of Ret-NH 2 and its amides, including a higher potency, specificity, and lower transcription activation. Our results also revealed that mice treated with Ret-NH 2 were completely resistant to the light-induced retina damage. As an experimental tool, Ret-NH 2 allows the replacement of the native chromophore with synthetic analogs in wild-type mice to better understand the function of the chromophore in the activation of rhodopsin and its metabolism through the retinoid cycle.In the photoreceptors of the vertebrate retina, light causes the isomerization of the visual pigments' chromophore, 11-cis-retinylidene, to all-trans-retinylidene, followed by the release of all-trans-retinal from the opsin binding pocket and its reduction to all-trans-retinol (McBee et al., 2001;Lamb and Pugh, 2004;Palczewski, 2006). Vitamin A (all-transretinol) diffuses to the retinal pigment epithelium (RPE), where it is esterified by lecithin/retinol acyltransferase (LRAT) to all-trans-retinyl esters and stored in the retinosomes (Imanishi et al., 2004a,b). All-trans-retinyl esters are isomerized to 11-cis-retinol in a reaction that involves an abundant 65-kDa RPE-specific protein, termed RPE65, proposed to be retinoid isomerase (Jin et al., 2005;Moiseyev et al., 2005;Redmond et al., 2005). To complete the cycle, 11-cis-retinol is then oxidized to its aldehyde. 11-cis-Retinal diffuses across the extracellular space to photoreceptors and recombines with opsins to regenerate visual pigments (McBee et al., 2001;Lamb and Pugh, 2004).The accumulation of fluorescent materials, lipofuscin, in the RPE is associated with aging. In humans, one of the major fluorescent compounds found most prominently in the macula is a pyridinium bis-retinoid, which is derived from two molecules of all-trans-retinal and one molecule of phosphatidylethanolamine, called N-retinylidene-N-retinyl ethanolamine (A2E) (Parish et al., 1998), w...

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“…The phenotype in rgr −/− mice is mild (94). These mice show reduced 11-cis-RAL and rhodopsin levels in the retina following light exposure, and increased all-trans-and 13-cis-retinyl esters in the RPE (94,95,135). Slightly decreased ERG responses are also seen, commensurate with the decreased levels of rhodopsin.…”

Section: Dominant and Recessive Rp Due To Mutations In The Rgr Genementioning

confidence: 99%

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Travis

Golczak

Moise

et al. 2007

Annu. Rev. Pharmacol. Toxicol.

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Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cisretinaldehyde to all-trans-retinaldehyde. Regeneration of visual chromophore following light exposure is dependent on an enzyme pathway called the retinoid or visual cycle. Our understanding of this pathway has been greatly facilitated by the identification of disease-causing mutations in the genes coding for visual cycle enzymes. Defects in nearly every step of this pathway are responsible for human-inherited retinal dystrophies. These retinal dystrophies can be divided into two etiologic groups. One involves the impaired synthesis of visual chromophore. The second involves accumulation of cytotoxic products derived from all-trans-retinaldehyde. Gene therapy has been successfully used in animal models of these diseases to rescue the function of enzymes involved in chromophore regeneration, restoring vision. Dystrophies resulting from impaired chromophore synthesis can also be treated by supplementation with a chromophore analog. Dystrophies resulting from the accumulation of toxic pigments can be treated pharmacologically by inhibiting the visual cycle, or limiting the supply of vitamin A to the eyes. Recent progress in both areas provides hope that multiple inherited retinal diseases will soon be treated by pharmaceutical intervention.

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Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

Cited by 34 publications

References 48 publications

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

Molecular pharmacodynamics of emixustat in protection against retinal degeneration

Effects of Potent Inhibitors of the Retinoid Cycle on Visual Function and Photoreceptor Protection from Light Damage in Mice

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

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