Sandbox Reserved 895: Difference between revisions

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== '''[1.1] The Retinoid (Visual) Cycle ''' ==

For humans to see, the retinoid (visual) cycle converts incident light entering in the eye into electrochemical signals that can be transmitted to the brain as neuronal impulses. The chemical reactions that take place within the retinoid cycle allows the regeneration of key intermediates to allow for vision to take place. Dysregulation of these chemical processes along with gene mutations is associated with disease. These diseases often lead to an ~~alterations~~ in vision causing blindness. Age related macular degeneration is an example of the dysregulation within the retinoid cycle. The 3-dimensional binding site of bovine RPE65 to an exogenous substrate (''R'')-emixustat shown in '''Figure 1A''' and '''Figure 1B'''. '''Figure 1C''' shows an the surface of bovine RPE65 where (''R'')-emixustat would enter to access the internal binding pocket of RPE65. Both '''Figure 1B''' and '''Figure 1C''' was generated using PyMol. (''R'')-emixustat is a drug candidate that was tested for the treatment of dry age related macular degeneration.

For humans to see, the retinoid (visual) cycle converts incident light entering in the eye into electrochemical signals that can be transmitted to the brain as neuronal impulses. The chemical reactions that take place within the retinoid cycle allows the regeneration of key intermediates to allow for vision to take place. Dysregulation of these chemical processes along with gene mutations is associated with disease. These diseases often lead to an alteration in vision causing blindness. Age-related macular degeneration is an example of the dysregulation within the retinoid cycle. The 3-dimensional binding site of bovine RPE65 to an exogenous substrate (''R'')-emixustat shown in '''Figure 1A''' and '''Figure 1B'''. '''Figure 1C''' shows the surface of bovine RPE65 where (''R'')-emixustat would enter to access the internal binding pocket of RPE65. Both '''Figure 1B''' and '''Figure 1C''' was generated using PyMol. (''R'')-emixustat is a drug candidate that was tested for the treatment of dry age related macular degeneration.

[[Image:RPE65_Emixustat_and_Palmitate_PyMOL.jpg|thumb|center|512 px|alt=Figure 1B: Emixustat and palmitate ester in Binding Pocket| '''Figure 1B:''' Bovine RPE65 Binding Pocket with Emixustat and palmitate ester generated in PyMOL using PDB: ''4RSV'']]

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In order to stimulate the phototransduction pathway, 11-''cis''-retinal must be absorbed into the body. 11-''cis''-retinal often referred as Vitamin A, is an important dietary vitamin that starts the cascade of phototransduction. Once absorbed into the body and brought to the photoreceptor outer segment (POS), 11-''cis''-retinal is conjugated to opsin to form the rhodopsin complex. Upon light incidence, 11-''cis''-retinal is converted though a photo-isomerization reaction into all-''trans''-retinal. The conversion of 11-''cis''-retinal to all-''trans''-retinal causes a conformation change in the rhodopsin complex. This conformation change activates a G-protein coupled protein transducing which triggers the subsequent phototransduction cascade. The generated all-''trans''-retinal then dissociates from the rhodopsin complex which frees the opsin protein to bind another 11-''ci''s-retinal molecule and restart the phototransduction cascade. All-''trans''-retinal must be converted back into 11-''cis''-retinal to serve as the chromophore for the phototransduction cascade. To regenerate 11-''cis''-retinal a series of enzyme catalyzed chemical reactions must take place. These reactions take place within the photoreceptor outer segment (~~hPOS~~) as well as the retinal pigment epithelium (hRPE).

In order to stimulate the phototransduction pathway, 11-''cis''-retinal must be absorbed into the body. 11-''cis''-retinal often referred as Vitamin A, is an important dietary vitamin that starts the cascade of phototransduction. Once absorbed into the body and brought to the photoreceptor outer segment (POS), 11-''cis''-retinal is conjugated to opsin to form the rhodopsin complex. Upon light incidence, 11-''cis''-retinal is converted though a photo-isomerization reaction into all-''trans''-retinal. The conversion of 11-''cis''-retinal to all-''trans''-retinal causes a conformation change in the rhodopsin complex. This conformation change activates a G-protein coupled protein transducing which triggers the subsequent phototransduction cascade. The generated all-''trans''-retinal then dissociates from the rhodopsin complex which frees the opsin protein to bind another 11-''cis''-retinal molecule and restart the phototransduction cascade. All-''trans''-retinal must be converted back into 11-''cis''-retinal to serve as the chromophore for the phototransduction cascade. To regenerate 11-''cis''-retinal a series of enzyme catalyzed chemical reactions must take place. These reactions take place within the photoreceptor outer segment (POS) as well as the retinal pigment epithelium (hRPE).

Following dissociation from opsin, all-''trans''-retinal is transported from the lumen of the photoreceptor disk though an ATP-cassette transporter 4 (''ABCA4''). The enzyme all-''trans''-retinol dehydrogenase (atRDH) reduces all-''trans''-retinal into all-''trans''-retinol. Another transporter enzyme, interphotoreceptor retinoid-binding protein (IRBP) facilitates the transporter of all-''trans''-retinol back into the hRPE. Within the hRPE, all-''trans''-retinol is esterified by the enzyme lecithin retinol acyltransferase (LRAT) to form all-''trans''-retinyl ester. RPE65 also known as retinoid isomerohydrolase (IMH) then converts all-''trans''-retinyl ester into 11-''cis''-retinol and palmityl acid. Following the RPE65 catalyzed reaction, 11-''cis''-retinol dehydrogenase (11-''cis''-RDH) oxidizes 11-''cis''-retinol into 11-''cis''-retinal. 11-''cis''-retinal is finally transported back into the photoreceptors to be conjugated to opsin to form the rhodopsin complex. This process is shown in Figure 2. <ref>DOI 10.1016/j.bbadis.2018.04.014</ref>

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@@ Line 12: / Line 12: @@
 == '''[1.1] The Retinoid (Visual) Cycle ''' ==
-For humans to see, the retinoid (visual) cycle converts incident light entering in the eye into electrochemical signals that can be transmitted to the brain as neuronal impulses. The chemical reactions that take place within the retinoid cycle allows the regeneration of key intermediates to allow for vision to take place. Dysregulation of these chemical processes along with gene mutations is associated with disease. These diseases often lead to an alterations in vision causing blindness. Age related macular degeneration is an example of the dysregulation within the retinoid cycle. The 3-dimensional binding site of bovine RPE65 to an exogenous substrate (''R'')-emixustat shown in '''Figure 1A''' and '''Figure 1B'''. '''Figure 1C''' shows an the surface of bovine RPE65 where (''R'')-emixustat would enter to access the internal binding pocket of RPE65. Both '''Figure 1B''' and '''Figure 1C''' was generated using PyMol. (''R'')-emixustat is a drug candidate that was tested for the treatment of dry age related macular degeneration.
+For humans to see, the retinoid (visual) cycle converts incident light entering in the eye into electrochemical signals that can be transmitted to the brain as neuronal impulses. The chemical reactions that take place within the retinoid cycle allows the regeneration of key intermediates to allow for vision to take place. Dysregulation of these chemical processes along with gene mutations is associated with disease. These diseases often lead to an alteration in vision causing blindness. Age-related macular degeneration is an example of the dysregulation within the retinoid cycle. The 3-dimensional binding site of bovine RPE65 to an exogenous substrate (''R'')-emixustat shown in '''Figure 1A''' and '''Figure 1B'''. '''Figure 1C''' shows the surface of bovine RPE65 where (''R'')-emixustat would enter to access the internal binding pocket of RPE65. Both '''Figure 1B''' and '''Figure 1C''' was generated using PyMol. (''R'')-emixustat is a drug candidate that was tested for the treatment of dry age related macular degeneration.
 [[Image:RPE65_Emixustat_and_Palmitate_PyMOL.jpg|thumb|center|512 px|alt=Figure 1B: Emixustat and palmitate ester in Binding Pocket| '''Figure 1B:''' Bovine RPE65 Binding Pocket with Emixustat and palmitate ester generated in PyMOL using PDB: ''4RSV'']]
@@ Line 18: / Line 18: @@
 [[Image:Binding_surface_overlap.jpg|thumb|center|512 px|alt=Figure 1C: Emixustat RPE65 binding pocket opening| '''Figure 1C:''' Bovine RPE65 Opening into Binding Pocket with the electron mesh of Emixustat outlined using PyMOL, PDB: ''4RSV'']]
-In order to stimulate the phototransduction pathway, 11-''cis''-retinal must be absorbed into the body. 11-''cis''-retinal often referred as Vitamin A, is an important dietary vitamin that starts the cascade of phototransduction. Once absorbed into the body and brought to the photoreceptor outer segment (POS), 11-''cis''-retinal is conjugated to opsin to form the rhodopsin complex. Upon light incidence, 11-''cis''-retinal is converted though a photo-isomerization reaction into all-''trans''-retinal. The conversion of 11-''cis''-retinal to all-''trans''-retinal causes a conformation change in the rhodopsin complex. This conformation change activates a G-protein coupled protein transducing which triggers the subsequent phototransduction cascade. The generated all-''trans''-retinal then dissociates from the rhodopsin complex which frees the opsin protein to bind another 11-''ci''s-retinal molecule and restart the phototransduction cascade. All-''trans''-retinal must be converted back into 11-''cis''-retinal to serve as the chromophore for the phototransduction cascade. To regenerate 11-''cis''-retinal a series of enzyme catalyzed chemical reactions must take place. These reactions take place within the photoreceptor outer segment (hPOS) as well as the retinal pigment epithelium (hRPE).
+In order to stimulate the phototransduction pathway, 11-''cis''-retinal must be absorbed into the body. 11-''cis''-retinal often referred as Vitamin A, is an important dietary vitamin that starts the cascade of phototransduction. Once absorbed into the body and brought to the photoreceptor outer segment (POS), 11-''cis''-retinal is conjugated to opsin to form the rhodopsin complex. Upon light incidence, 11-''cis''-retinal is converted though a photo-isomerization reaction into all-''trans''-retinal. The conversion of 11-''cis''-retinal to all-''trans''-retinal causes a conformation change in the rhodopsin complex. This conformation change activates a G-protein coupled protein transducing which triggers the subsequent phototransduction cascade. The generated all-''trans''-retinal then dissociates from the rhodopsin complex which frees the opsin protein to bind another 11-''cis''-retinal molecule and restart the phototransduction cascade. All-''trans''-retinal must be converted back into 11-''cis''-retinal to serve as the chromophore for the phototransduction cascade. To regenerate 11-''cis''-retinal a series of enzyme catalyzed chemical reactions must take place. These reactions take place within the photoreceptor outer segment (POS) as well as the retinal pigment epithelium (hRPE).
 Following dissociation from opsin, all-''trans''-retinal is transported from the lumen of the photoreceptor disk though an ATP-cassette transporter 4 (''ABCA4''). The enzyme all-''trans''-retinol dehydrogenase (atRDH) reduces all-''trans''-retinal into all-''trans''-retinol. Another transporter enzyme, interphotoreceptor retinoid-binding protein (IRBP) facilitates the transporter of all-''trans''-retinol back into the hRPE. Within the hRPE, all-''trans''-retinol is esterified by the enzyme lecithin retinol acyltransferase (LRAT) to form all-''trans''-retinyl ester. RPE65 also known as retinoid isomerohydrolase (IMH) then converts all-''trans''-retinyl ester into 11-''cis''-retinol and palmityl acid. Following the RPE65 catalyzed reaction, 11-''cis''-retinol dehydrogenase (11-''cis''-RDH) oxidizes 11-''cis''-retinol into 11-''cis''-retinal. 11-''cis''-retinal is finally transported back into the photoreceptors to be conjugated to opsin to form the rhodopsin complex. This process is shown in Figure 2. <ref>DOI 10.1016/j.bbadis.2018.04.014</ref>