retinylamine has been researched along with emixustat* in 2 studies
2 other study(ies) available for retinylamine and emixustat
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Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function.
Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in Topics: Adaptation, Physiological; Animals; cis-trans-Isomerases; Diterpenes; Enzyme Inhibitors; GTP-Binding Protein alpha Subunits; Membrane Proteins; Mice; Mice, Inbred C57BL; Oxidoreductases; Phenyl Ethers; Photoreceptor Cells; Propanolamines; Sciuridae; Transducin; Vision, Ocular | 2018 |
Catalytic mechanism of a retinoid isomerase essential for vertebrate vision.
Visual function in vertebrates is dependent on the membrane-bound retinoid isomerase RPE65, an essential component of the retinoid cycle pathway that regenerates 11-cis-retinal for rod and cone opsins. The mechanism by which RPE65 catalyzes stereoselective retinoid isomerization has remained elusive because of uncertainty about how retinoids bind to its active site. Here we present crystal structures of RPE65 in complex with retinoid-mimetic compounds, one of which is in clinical trials for the treatment of age-related macular degeneration. The structures reveal the active site retinoid-binding cavity located near the membrane-interacting surface of the enzyme as well as an Fe-bound palmitate ligand positioned in an adjacent pocket. With the geometry of the RPE65-substrate complex clarified, we delineate a mechanism of catalysis that reconciles the extensive biochemical and structural research on this enzyme. These data provide molecular foundations for understanding a key process in vision and pharmacological inhibition of RPE65 with small molecules. Topics: Animals; Binding Sites; Biocatalysis; cis-trans-Isomerases; Crystallography, X-Ray; Diterpenes; Ligands; Light; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Palmitates; Phenyl Ethers; Propanolamines; Protein Binding; Protein Conformation; Retinal Pigment Epithelium; Retinoids; Stereoisomerism; Vision, Ocular | 2015 |