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Review
, 114 (1), 194-232

Chemistry of the Retinoid (Visual) Cycle

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Review

Chemistry of the Retinoid (Visual) Cycle

Philip D Kiser et al. Chem Rev.

Figures

Figure 1
Figure 1
Mevalonate pathway for the synthesis of IPP. Two molecules of acetyl-CoA are joined together to form acetoacetyl-CoA (i) in a reaction catalyzed by thiolase with the release of free CoA (CoASH). A third molecule of acetyl-CoA is added by 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase to form HMG-CoA (ii). Compound ii is reduced by HMG-CoA reductase in an NADPH-dependent manner to form (R)-mevalonate (iii), which is the rate-limiting step of the pathway. Compound iii is sequentially phosphorylated by mevalonate kinase and phosphomevalonate kinase to form (R)-mevalonate-5-diphosphate (iv). Finally, iv is decarboxylated by mevalonate-5-diphosphate decarboxylase in an ATP-dependent manner to form IPP (v). Coloring of oxygen atoms is intended to assist in tracking of the chemical origin of the carbon skeleton. P, phosphoryl group; OPi, inorganic phosphate.
Figure 2
Figure 2
MEP (nonmevalonate) pathway for the synthesis of IPP and DMAPP. First, d-glyceraldehyde-3-phosphate (i) is condensed with pyruvate to form 1-deoxy-d-xylulose-5-phosphate (DOXP, ii) catalyzed by 1-deoxy-d-xylulose-5-phosphate synthase (DXS) using a thiamine diphosphate cofactor with the loss of CO2. ii is isomerized and reduced by DOXP-isomeroreductase (IspC) in an NADPH-dependent manner to form 2C-methyl-d-erythritol-4-phosphate, which is then conjugated with CTP to form 4-diphosphocytidyl-2C-methyl d-erythritol (iv) in a reaction catalyzed by 2C-methyl-d-erythritol cytidylyltransferase (IspD). iv is then phosphorylated to form 4-diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate (v) by 4-diphosphocytidyl-2C-methyl-d-erythritol kinase (IspE). v is cyclized with the loss of CMP to form 2C-methyl-d-erythritol-2,4-cyclodiphosphate (vi) by 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF). vi is then reduced with cleavage of the cyclodiphosphate moiety to form 1-hydroxy-2-methyl-2-(E)-butenyl diphosphate (vii) by the iron-sulfur enzyme IspG using ferrodoxin as a cofactor. Finally, vii is further reduced by a second iron–sulfur protein IspH, giving a mixture of IPP (viii) and dimethylallyl diphosphate (DMAPP, ix). The red colored oxygen atom is intended to assist in tracking of the chemical origin of the carbon skeleton. P, phosphoryl group; PPi, inorganic pyrophosphate.
Figure 3
Figure 3
Reversible isomerization of IPP (i) into DMAPP (ii). The reaction, catalyzed by IPP/DMAPP isomerase, is thought to proceed via a protonated carbocationic intermediate shown in brackets.
Figure 4
Figure 4
The carotenoid branch of isoprenoid biosynthesis. Synthesis of β,β-carotene begins with the sequential condensation of a single DMAPP molecule (i) with three IPP molecules to form C20 geranylgeranyl diphosphate (ii, GGPP) catalyzed by GGPP synthase (CrtE). Next, two GGPP molecules are combined in a head-to-head fashion to form C40 15-cis-phytoene (iii, shown in the all-trans configuration for ease of presentation) in a reaction catalyzed by phytoene synthase (CrtB), which is the first committed step in carotenoid biosynthesis. In bacteria, phytoene is converted to all-trans-lycopene (iv) by a series of desaturation and isomerization steps catalyzed by CrtI. In plants this conversion is catalyzed by phytoene desaturase and ζ-carotene desaturase together with the isomerases ζ-carotene isomerase and CrtIso. Finally, lycopene is converted to β,β-carotene (v) in two steps by lycopene β-cyclase. Lycopene is also a substrate for lycopene ε-cyclase, which catalyzes formation of δ-carotene (not shown).
Figure 5
Figure 5
Retinoid metabolism in vertebrates. Dietary all-trans-β,β-carotene (i), obtained primarily from plants, is oxidatively cleaved in a symmetric manner by β-carotene monooxygenase I (BCMO I), yielding two molecules of all-trans-retinal (ii). Retinal can reversibly combine with an amino group to form a retinyl imine (Schiff base) (iv). Retinal is also subject to oxidation and reduction to form retinoic acid (iii) and retinol (vitamin A) v, respectively, the latter in a physiologically reversible manner. Retinoic acid can be converted into several conjugated and/or oxidized derivatives, some of which exert biological effects. Retinol also can be converted into several derivatives including retro-retinoids, saturated retinols, and phosphate conjugates. Retinol is also reversibly esterified to produce retinyl esters (vi), the main storage form of vitamin A in the body.
Figure 6
Figure 6
HPLC-based separation and detection of retinoids. (A) The main classes of retinoid isomers commonly found in experimental samples that can be distinguished by analytical methods. (B) Elution profiles of retinol, retinal, and retinal oxime isomers from a normal phase HPLC column with an isocratic flow of 10% ethyl acetate/hexane. Primary analytical methods of retinoid identification and quantification include UV/vis spectroscopy and mass spectrometry. (C) UV/vis absorbance spectra of selected retinoids reveal characteristic differences in absorbance maxima and overall shape of the spectra that are used to classify the chemical and geometric form of retinoids. (D) Electrospray ionization of retinol and retinyl esters triggers water or carboxylate dissociation, resulting in the predominant parent ion of m/z = 269 [M – 17]+, whereas retinal exhibits the expected molecular ion of m/z = 285 [M + H]+. Characteristic MS/MS fragmentation patterns of the parent ions are shown in the bottom panels. The typical m/z = 161 fragment of retinal in MS/MS spectra is indicative of ionone ring loss from the parent ion.
Figure 7
Figure 7
Conversion of all-trans-retinol (i) into anhydroretinol (ii) and retro-retinol (iii) in the presence of acid via carbocationic intermediates.
Figure 8
Figure 8
Production of anhydroretinol from all-trans-retinol catalyzed by retinol dehydratase. First, a sulfo group is transferred to all-trans-retinol (i) to form retinyl sulfate (ii). Loss of sulfate then generates a carbocationic intermediate (iii) that, in the confines of the enzyme active site, preferentially rearranges with loss of a proton to form anhydroretinol (iv).
Figure 9
Figure 9
Generation of retinoid isomers from all-trans-retinal. The all-trans form of retinoids is the lowest in free energy and thus predominates at equilibrium. Formation of retinoid isomers can be facilitated chemically by treatment with I2, sulfhydryls, and trifluoroacetic acid, or by exposure to light. The composition of retinal isomers found at equilibrium is reported after Rando et al. and Deval et al.
Figure 10
Figure 10
Retinoid isomerization by sequential saturation–desaturation chemistry. This strategy is used, for example, by plant lycopene isomerase (CrtIso).
Figure 11
Figure 11
Conversion of all-trans-retinol (i) into all-trans-(R)-13,14-dihydroretinol (ii) by RetSat, an enzyme evolutionarily related to CrtIso.
Figure 12
Figure 12
Comparison of photoreceptor structure between invertebrates represented by Drosophila and vertebrates represented by man. Invertebrates utilize a rhabdomeric photoreceptor cell whereas vertebrate photoreceptors are modified ciliary cells. Notably, a few invertebrates, such as Amphioxus, employ ciliary photoreceptors.
Figure 13
Figure 13
Structure of the mammalian retina. The retina consists of several layers of neuronal cells. The innermost photoreceptor layer is embedded in an epithelial monolayer, known as the RPE. Electron micrographs show stacks of membranous disks within ROS (left) and COS (right), which contain visual pigments and the associated phototransduction machinery. The leftmost and rightmost electron micrographs display the bacillary structure of the outer segments and their interaction with the RPE, respectively. A portion of this figure is reproduced with permission from ref (235). Copyright 2009 Elsevier.
Figure 14
Figure 14
Structure of the RPE. Electron micrographs show the apical processes that extend out from the cell body and interdigitate with photoreceptor outer segments (A, lower resolution; B, higher resolution). In part C, a cross section though an RPE cell shows its cuboidal morphology and numerous melanin granules. Panel D depicts interactions between an RPE cell and photoreceptor outer segments at high resolution. Transmission electron micrographs from a C57BL/6J mouse retina were taken at postnatal days 60–66. The RPE cell intimately interacts with the photoreceptor outer segment via apical microvilli, thereby supporting photoreceptor cell function.
Figure 15
Figure 15
Retinoid (visual) cycle. Enzymes (red) and binding proteins (blue) involved in 11-cis-retinal regeneration are found in both photoreceptor and RPE cells. Metabolic transformations occurring in the RPE take place in the smooth ER, where key enzymes of the visual cycle are located. PC, phosphotidylcholine.
Figure 16
Figure 16
Putative cone-specific retinoid (visual) cycle. This metabolic pathway is postulated to involve enzymes located in cone photoreceptor and Müller glial cells. The proposed direct isomerization of all-trans-retinol into 11-cis-retinol is a key difference between this pathway and the canonical retinoid cycle.
Figure 17
Figure 17
Retinoid-containing structures found in healthy and diseased retinas imaged by two-photon microscopy. The top panel shows a schematic of the photoreceptor outer segment–RPE interaction with retinoid-containing retinosomes (red ovals) and retinoid conjugate-containing particles (orange circles) shown with their approximate dimensions (bottom left). In healthy eyes (WT), numerous peripherally located retinosomes (punctuate green spots) can be visualized. The number and size of these vesicles are elevated in Rpe65–/– mice, owing to excessive accumulation of retinyl esters (bottom center). In Abca4–/–Rdh8–/– mice with delayed all-trans-retinal clearance, retinoids are diffusely present throughout the cell, presumably in the form of all-trans-retinal-conjugates (bottom right). Scale bars represent 20 μm.
Figure 18
Figure 18
Structure and photoactivation of rhodopsin. (a) Crystal structure of ground-state bovine rhodopsin. The Schiff base-linked 11-cis-retinal chromophore is shown in stick representation (red). (b) Photoactivation and regeneration of rhodopsin. (c) Primary conformational changes observed between ground-state (red, PDB accession code 1U19) and activated, meta II-like (yellow, PDB accession code 3PXO) rhodopsin.
Figure 19
Figure 19
Chemical changes in the rhodopsin chromophore during photoactivation. The pathway is initiated when 11-cis-retinylidene (i) absorbs a photon, leading to cis/trans isomerization. Then the Glu113 counterion of the protonated Schiff base becomes protonated, leading to the formation of Meta I rhodopsin (ii). Meta I, in turn, can convert to Meta II rhodopsin (iii), the active signaling form of rhodopsin, or, rarely, to Meta III rhodopsin (iv), a non-signaling form of rhodopsin. Both forms decay through a carbinol ammonium intermediate (v) to form a non-covalent opsin–all-trans-retinal complex (vi), which then dissociates to yield free all-trans-retinal and opsin (vii).
Figure 20
Figure 20
Structure and catalytic mechanism of RDHs. (a) Cartoon representation of a representative SDR family member (type 1 17-β-hydroxysteroid dehydrogenase, PDB accession code 1A27). (b) Hypothetical structure of an RDH with bound nucleotide (NAD(H) or NADP(H)) and retinoid (all-trans-retinol or all-trans-retinal) substrate. The structures in panels a and b are depicted in the same orientation. (c) Reversible transfer of hydride from the S4-face of the nucleotide to all-trans-retinal to produce pro-R-all-trans-retinol.
Figure 21
Figure 21
Sequence alignment of known vertebrate RDH’s of the SDR family. Glycine residues of the conserved TGXXXGXG, nucleotide-binding motif are highlighted in blue, whereas residues comprising the catalytic tetrad are highlighted in orange.
Figure 22
Figure 22
Sequence alignment and structure of LRAT-like acyltransferase enzymes. A protein sequence alignment of all LRAT-like proteins encoded in the human genome is displayed on the left, showing conserved His and Cys residues (orange) that constitute the catalytic triad of this enzyme family. Hydrophobic C-terminal membrane-anchoring sequences are colored green. The crystallographic structure of human HRASLS3 is shown on the right with the carbon atoms of residues comprising the catalytic triad colored orange.
Figure 23
Figure 23
Catalytic mechanism of LRAT. The enzyme utilizes a ping pong bi bi catalytic mechanism. In this reaction, the active site Cys nucleophile, which was crystallographically observed to exist in two conformations (i), attacks the sn-1 ester group to form a tetrahedral intermediate (ii) that collapses into a stable acyl-enzyme intermediate with liberation of Lyso-PC (iii). The negatively charged oxygen is stabilized by an oxyanion hole (dotted curve in ii). Next, all-trans-retinol binds to the active site and is activated to produce a nucleophilic attack on the acyl-enzyme thioester bond (iv), resulting in formation of a tetrahedral intermediate again stabilized by an oxyanion hole (v) that collapses to release the all-trans-retinyl ester and regenerate the nucleophilic Cys residue. Catalytic His residues likely promote catalysis by increasing the nucleophilicity of the active site Cys and by serving as general proton donors/acceptors.
Figure 24
Figure 24
Formation of retinyl esters catalyzed by acyl-CoA/retinol acyltransferase.
Figure 25
Figure 25
Structural alignment of CCO family members. (A) Iron-binding His residues are highlighted in orange, and second sphere Glu residues are highlighted in blue. (B) Structural superposition of CCO members of known structure (RPE65, orange; ACO, blue; VP14, pink). These enzymes adopt a 7-bladed β-propeller fold (blades labeled with Roman numerals) with a helical cap on the top face of the propeller that houses the active site and membrane-binding domain (curved, dashed line), which surrounds the active site entrance indicated by a yellow-green arrow. The iron cofactor located at the center of the propeller is coordinated by four conserved His residues (green). The two views in panel B differ by a 90° horizontal rotation.
Figure 26
Figure 26
Crystal structure of RPE65 obtained in the presence of native microsomal membranes. Conserved His residues (green sticks) are shown coordinating the catalytic iron (orange spheres). The dimeric structure of RPE65 has been observed in multiple crystal forms. This results in a parallel orientation of the membrane-binding surfaces (brown sticks), which likely promotes membrane attachment. The membrane-binding surface surrounds the entrance to the active site cavity outlined in magenta mesh.
Figure 27
Figure 27
RPE65 active site cavity. The cavity (gray mesh) is predominantly lined by hydrophobic residues that facilitate retinyl ester uptake from the membrane. The cavity passes by the catalytic iron and terminates deep inside the enzyme core. Residues colored green have been shown through mutagenesis studies to be important in maintaining the 11-cis specificity of RPE65 isomerase activity.
Figure 28
Figure 28
Acyl versus O-alkyl ester cleavage.
Figure 29
Figure 29
Binuclear nucleophilic substitution mechanism of retinoid hydrolysis/isomerization. The key feature is formation of a covalent enzyme–retinoid intermediate that allows rotation around the 11–12 bond.
Figure 30
Figure 30
Unimolecular nucleophilic substitution mechanism of retinoid isomerization. The key feature is the generation of a carbocation (retinylic cation) intermediate with lowered bond order that allows rotation around the 11–12 bond to occur. Dissociation of the ester moiety can be facilitated by a Brønsted or Lewis acid catalyst (X).
Figure 31
Figure 31
Radical cation mechanism of retinoid isomerization.
Figure 32
Figure 32
Structures of retinoid-binding proteins involved in the retinoid cycle. (A) RBP4, (B) Module 2 of X. laevis IRBP, (C) CRBP I, and (D) CRALBP. Bound retinoids are depicted as sticks with carbon atoms colored orange.
Figure 33
Figure 33
Structure and function of ABCA4. (A) Two-dimensional topology diagram of ABCA4. Positions of the Walker A motifs are indicated by blue dashed lines within the CDs. Glycosylation sites are marked with red stars, and an intramolecular disulfide bridge is indicated by S–S. ECD, exocytoplasmic domain; CD, cytoplasmic domain. (B) Electron microscopic structure of ABCA4 and its dimensions relative to a ROS disk rim. TMDs, transmembrane domains. (C) Structural differences in ABCA4 in the absence and presence of ATP. (D) Role of ABCA4 in the visual cycle and pathology of elevated all-trans-retinal. ABCA4 flips the all-trans-retinal–PE complex, a product of all-trans-retinal (red line structure) condensation with PE (black line structure with blue sphere indicating the headgroup), to the outer leaflet of the disk membrane, allowing dissociation of the complex and subsequent reduction of all-trans-retinal to all-trans-retinol, which then reenters the visual cycle (left). Retinal pathology is observed in mice lacking ABCA4 and RDH8 activities due to accumulation of all-trans-retinal and its lipid adducts (right).
Figure 34
Figure 34
Mechanism of A2E formation from all-trans-retinal and phosphatidylethanolamine (R-NH2).
Figure 35
Figure 35
Mechanism of all-trans-retinal dimer formation from all-trans-retinal and phosphatidylethanolamine (R-NH2).
Figure 36
Figure 36
Retinal diseases caused by defects in visual cycle enzymes. Therapeutic agents used in the treatment of these conditions are indicated.
Figure 37
Figure 37
Key proteins involved in the transport of retinol from the liver to target tissues. Retinol travels in the circulation bound to RBP. In turn, RBP complexes with a transthyretin (TTR) tetramer, which prevents filtration of RBP across the glomeruli of the kidney. Holo-RBP can dissociate from the TTR tetramer and bind to the retinol membrane transporter, STRA6. all-trans-Retinol is picked up on the cytoplasmic side of STRA6 by CRBP, which shuttles the retinoid to the ER of the RPE. There it is esterified by LRAT to form all-trans-retinyl-esters, which are either used as substrates for visual chromophore production or stored in lipid bodies known as retinosomes: atROL, all-trans-retinol; atRE, all-trans-retinyl ester.

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