2.1. Mevalonate and Nonmevalonate Pathways

Naturally occurring carotenoids are all synthesized from two basic5-carbon precursors: isopentenyl diphosphate (IPP) and its isomerdimethylallyl diphosphate (DMAPP).⁸⁷ Amultitude of additional compounds, including steroids, ubiquinones,and chlorophylls, are also synthesized from these isoprene precursorsand are thus collectively referred to as isoprenoids or terpenoids.^88,89 Until the early 1990s it was believed that isoprenoid precursorswere synthesized exclusively through the mevalonate pathway, a seriesof enzymatically catalyzed reactions in which three molecules of acetate,in the form of acetyl-coenzyme A (acetyl-CoA), are condensed and modifiedby reduction, phosphorylation, and decarboxylation to generate IPP⁸⁹ (Figure1). Researchin eubacteria and plants then revealed a second metabolic route forIPP synthesis referred to as the methylerythritol 4-phosphate (MEP)or nonmevalonate pathway, which utilizes the triose derivative,d-glyceraldehyde 3-phosphate along with pyruvate as startingmaterials⁹⁰⁻⁹⁴ (Figure2). Following condensation of thesetwo molecules, a methyl isomerization reaction occurs that convertsthe initially linear carbon chain into an isopentyl linkage.^95,96 Subsequent reduction, CDP transfer, phosphorylation, and reductionserve to eliminate hydroxyl functional groups and introduce a diphosphategroup to generate IPP as well as DMAPP in about a five to one ratio.⁹⁷ In many cases, a particular organism encodesthe enzymes for only one of these two metabolic pathways in its genome.⁹⁰ Metazoans, fungi, and archaea rely exclusivelyon the mevalonate pathway for isoprenoid biosynthesis, whereas cyanobacteriaand algae make sole use of the MEP pathway.⁹⁸ Depending on the species, eubacteria and protozoa can employ eitherof the two pathways in a mutually exclusive fashion.⁹⁹ However, most eubacteria utilize the MEP pathway.⁹⁹ In higher plants, most cytosolic IPP and DMAPPare derived from the mevalonate pathwayvia enzymesencoded by genomic DNA. By contrast, these isoprene compounds aresynthesized through the MEP pathway in plastids of plants as a consequenceof the evolutionary relationship of plastids to cyanobacteria.¹⁰⁰ However, mixing of cytosolic and plastid isoprenoidprecursors has been reported.^101,102 Most carotenoids consumedby humans are synthesized from MEP-derived IPP and DMAPP.

IPP and DMAPP differ only in the position of an alkene doublebondand are thus classified as geometric isomers (Figure3). Enzymes known as IPP isomerases (IDIs) catalyze the reversibleisomerization of IPP into DMAPP. For organisms that solely use themevalonate pathway for isoprene biosynthesis, IDIs are essential forproduction of DMAPP because only IPP is generated through this pathway.Although both IPP and DMAPP are producedvia theMEP pathway, IDIs are still required to generate the proper IPP/DMAPPratio for isoprenoid biosynthesis.^103,104 Two structurallyunrelated enzymes, called IDI type 1 and IDI type 2, can each carryout the reaction.¹⁰⁵ Type 1 IDIs were thefirst to be characterized and rely on an active site Cys residue aswell as divalent cations for their catalytic function.¹⁰⁶ Biochemical and crystallographic analyses oftype I IDI indicate that an active site, metal-binding Glu residuetransfers a proton to the alkene π bond of IPP, generating atertiary carbocation or carbocation-like intermediate.^107,108 Abstraction of a proton from C2 of the isoprene skeleton by an activesite Cys residue regenerates the alkene forming DMAPP.^109,110 Isotope labeling studies demonstrated that the proton transpositionoccurs in an antarafacial manner, a mechanism consistent with theplacement of catalytic groups in the active site of type I IDIs.¹¹¹ Type II IDIs are a more recently discoveredclass of enzymes that catalyze the same reaction as type I IDIs butare structurally and evolutionarily unrelated.^105,106 In contrast to type I IDIs, type II enzymes rely on flavin mononucleotide(FMN_red) and NADPH as well as divalent cations as cofactorsto perform catalysis.¹⁰⁵ The dependenceon these nucleotide cofactors was somewhat surprising given that IPPto DMAPP isomerization does not involve net redox changes. Free radicalmechanisms involving transient abstraction of a hydrogen atom¹¹² as well as protonation–deprotonation(carbocation intermediate) mechanisms^113,114 have beenproposed as a means to effect the double bond shift. The involvementof carbocation intermediates turns out to be a major theme in theenzymatic isomerization of isoprenoids.

2.2. CarotenoidBiosynthesis

The biosynthesisof carotenoids from IPP and DMAPP begins with the condensation ofone molecule of DMAPP with three molecules of IPP catalyzed by theenzyme geranylgeranyl diphosphate synthase to form geranylgeranyldiphosphate (GGPP) (Figure4).⁸⁷ In some plant species, geranyl diphosphate is synthesizedfirst by the enzyme geranyl diphosphate synthase and then elongatedby the addition of two IPP molecules in a GGPP synthase-catalyzedreaction. These enzymes belong to the prenyl transferase family, whichuse divalent cations, such as Mg²⁺ or Mn²⁺,to carry out the condensation of isoprenoid precursors.¹¹⁵ Mechanistically, the divalent cation polarizesthe diphosphate moiety of DMAPP to facilitate its dissociation withconsequent formation of an electrophilic carbocation intermediate.^116,117 Proper positioning of IPP in the active site facilitates a nucleophilicattack of the alkene π bond electrons on C1 of the isoprenecarbocation, resulting in formation of a new carbon–carbonsingle bond. Deprotonation of the diphosphate-containing unit resultsin C1–C2 π bond formation, allowing chain elongationto continue in the presence of appropriate enzymes. Two moleculesof GGPP are then joined in a head to head fashion to form phytoenein a reaction catalyzed by the enzyme phytoene synthase, which isthe first committed step in the synthesis of carotenoids.¹⁰⁰ This reaction again features a carbocationor carbocation-like intermediate that reacts with a second GGPP tofrom a cyclopropylcarbonyl diphosphate compound (prephytoene diphosphate).^118−120 This compound breaks down with loss of pyrophosphate and a protonto produce 15-cis-phytoene.¹²¹ The colorless, C₄₀ tetraterpenoid product is then subjectedto a series of desaturation and isomerization reactions that culminatein the production ofall-trans-lycopene, the immediateprecursor of β,β-carotene. In bacteria, a single enzymecalled carotene desaturase (CrtI) is responsible for conversion ofphytoene into lycopene. In plants, two desaturase enzymes called phytoenedesaturase (PDS) and ξ-carotene desaturase (ZDS)¹²² and two isomerases called ξ-caroteneisomerase¹²³ and carotenoid isomerase (CrtIso)¹²⁴ together convert phytoene into lycopene.⁸⁷ Interestingly, CrtIso shares significant sequencehomology with the carotene desaturase (CrtI) as well as a mammalianenzyme known as retinol desaturase (RetSat).^63,125 Lycopene, a compound with a red hue conferred by a set of 11 conjugateddouble bonds, is transformed into β,β-carotene by an enzymeknown as lycopene-β-cyclase.^126,127 Althoughnot a reaction that involves net redox changes, the cyclization performedby lycopene-β-cyclase is dependent on an NAPDH cofactor.¹²⁸ In keeping with the general theme of terpenoidisomerization, lycopene cyclization reactions also occur through carbocationintermediates.¹²⁹

2.3. Retinoid Metabolism in Vertebrates

Mammals efficiently utilize both preformed vitamin A in the formofall-trans-retinyl esters and pro-vitamin A carotenoids(mainly β,β-carotene) to sustain the body pool of vitaminA.¹³⁰ Unlike retinyl esters, which arehydrolyzed to retinol in the small intestine followed by rapid absorptionby enterocytes, uptake of carotenoids is mediated and regulated byscavenger receptor class-B type-I (SR-BI).^131,132 Upon absorption by enterocytes, β,β-carotene undergoesoxidative cleavage catalyzed by β,β-carotene 15,15′-monooxygenase(BCMO1).^133,134 This symmetric split of thecarotenoid produces two molecules ofall-trans-retinalthat subsequently enter vitamin A metabolic pathways (Figure5).

The diverse functions of retinoids are carried out by a fewphysiologicallyactive metabolites ofall-trans-retinol that areproduced by enzymatic modification of the functional groups of thisvitamin and geometric isomerization of its polyene chain. Oxidationofall-trans-retinal catalyzed by retinaldehyde dehydrogenases(RALDHs) leads to formation ofall-trans-retinoicacid, a ligand for nuclear retinoic acid receptors (RARs) that, coupledwith retinoid X receptors (RXRs), bind to retinoic acid response elementson the promoter region of target genes and regulate their transcription.^135,136 Becauseall-trans-retinoic acid formation is irreversible,an excess of this active retinoid can be cleared only by its furtherconversion to more polar metabolites through oxidation by cytochromeP450 (CYP26) and/or glucuronidation by UDP-glucuronosyl transferases(UGTs).^137,138 An alternative metabolic pathway ofall-trans-retinal leads to formation of 11-cis-retinal, a visual chromophore that couples to rod and cone opsinsto form photosensitive pigments.^139−141 The thermodynamicallyunfavorable isomerization of the 11–12 double bond does notoccur at the aldehyde levelin vivo.¹⁴² Instead,all-trans-retinalis first reduced toall-trans-retinol by short-chaindehydrogenase/reductase (SDR) or alcohol dehydrogenase enzymes.^136,143,144 Subsequent esterification ofall-trans-retinol, mainly by lecithin/retinol acyltransferase(LRAT), provides both a major storage form of retinoids in the bodyand a direct substrate for RPE65-dependent enzymatic isomerizationof the retinoid polyene chain.^145−148 Multiple additional endogenous retinoidmetabolites are derived fromall-trans-retinol. Theseincludeall-trans-13,14-dihydroretinol produced bysaturation of the double bond by RetSat. Other examples are retro-retinoids,such as anhydroretinol and 14-hydroxy-4,14-retro-retinol. Though themolecular identities of enzymes involved in the production of retro-retinoidsin vertebrates are currently unknown, these metabolites have beenshown to regulate lymphocyte proliferation.^149−151 Transfer of a phospho group ontoall-trans-retinolresults in formation of retinyl monophosphate that has been detectedin the liver of rodents.^152,153 Glycophospholipidsconsisting of a retinol moiety linked by a phosphodiester bond tomannose or galactose were postulated to function in the transfer ofsugar units onto proteins to form some glycoproteins.¹⁵⁴

3.1. Geometric Isomers of Retinoids

Progressin understanding vitamin A metabolism would not be possible withoutdevelopment of adequate analytical methods that allow separation,detection, and quantification of retinoids. Such methods have graduallyadvanced since the discovery of vitamin A about 100 years ago. A complicationis that retinoids exist in several geometrical configurations withdifferently modified functional groups (Figure6A). Lipophilic compounds soluble in organic solvents, including retinoland its esters, were initially separated by thin-layer chromatographyon alumina- and silica-based stationary phases.^155,156 However, introduction of modern high performance liquid chromatography(HPLC) techniques in the early 1970s together with standardized commerciallyavailable compact stationary phase columns enabled precise, reproducibleanalyses of vitamin A metabolites and, most importantly, determinationof their isomeric composition.^157−160 Today retinoids can be separated under numerouschromatographic conditions (summarized in refs (160 and161)) optimized fornormal and reverse-phase columns. Selection of the most appropriatemethodology depends on the chemical properties of the particular retinoidas well as the source of the biological sample. The eye exhibits anespecially complex retinoid composition. The highest resolution methodfor separating retinyl esters, retinal, and retinol as well as theirisomers present in the eye is normal phase HPLC (Figure6B).¹⁶¹ The strength of an analyte’sinteraction with the silica stationary phase depends not only on itsfunctional groups but also on steric factors and the structure ofthe molecule. This feature is especially important for separationof molecules that are chemically similar but physically different,e.g. geometric isomers. Moreover, this methodology provides uniqueflexibility in tuning chromatographic conditions by adjusting thepolarity of the mobile phase, routinely composed of hexane and ethylacetate. Highly hydrophobic hexane simplifies the tissue homogenateextraction procedure and greatly reduces sample complexity withoutsacrificing overall analytical performance.¹⁶²

Retinoid detection, identification,and quantification are simplifiedby their characteristic spectral properties (Figure6C and D). The conjugated polyene chain contributes to relativelystrong absorption at ultraviolet (UV) and visible (Vis) wavelengths.Thus, absorbance maxima as well as the overall shape of the spectraprovide valuable information about the number of conjugated doublebonds and allow identification of the isomeric states of the compound.UV/Vis detection offers a limit of retinoid quantification at a lowpicomolar range through most photodiode array detectors and providesexcellent linearity over a wide range of concentrations (2–1500pmol) (Figure6C).¹⁶³ A complementary analytical method allowing precise molecular identificationand quantification of retinoids is mass spectrometry (MS). The greatestadvantage of MS coupled to HPLC is sensitivity in the low femtomolarrange. Moreover, modern tandem mass spectrometry offers definitivemolecular identification based on the induced fragmentation patternof the precursor ion (Figure6D).

3.2. Retro- and anhydro-retinols

In the1920s two groups^164,165 made the discovery that vitaminA-containing solutions, in the presence of Brønsted and Lewisacids, undergo a color change from pale yellow (λ_max ∼ 325 nm) to brilliant blue (λ_max ∼600 nm). The blue color is semistable with an effective lifetime ofup to ∼3 min when chloroform is used as a solvent.¹⁶⁶ This color change, when initiated using antimonytrichloride as the Lewis acid, is known as the Carr–Price reactionand was a primary means of retinol detection and quantification priorto the advent of chromatographic methods.¹⁶⁷ Investigation into the mechanism of the reaction underlying thecolor change revealed that the hydroxyl moiety of retinol readilycombines with acids (e.g., protons or antimony), converting it intoa good leaving group.¹⁶⁶ Hydroxyl dissociationgenerates a short-lived retinylic cation that can undergo proton eliminationto form anhydroretinol (Figure7). Anhydroretinolcan then undergo further chemical reactions to generate relativelylong-lived, blue-color species.¹⁶⁸ In additionto anhydroretinol, direct protonation of the 13,14 retinol doublebond followed by proton elimination at C4 leads to formation retro-retinol(Figure7). Generation of the retinylic cationcan also be accomplished by flash photolysis of retinyl acetatevia heterolytic carbon–oxygen bond dissociation¹⁶⁹ or by reactions of protons, released by radiolyticpulses, with retinol or retinyl acetate.¹⁷⁰ The special location of the retinol hydroxyl group with respectto the conjugated polyene chain makes it a much better leaving groupthan is typical for regular aliphatic alcohols. Upon dissociation,the resulting retinylic cation is stabilized by extensive delocalizationalong the polyene chain with a half-life on the nanosecond time scale.^169,171 Hydroxyl dissociation can also be facilitated by its conjugationwith an electron-withdrawing group, for example a sulfo moiety, asoccurs catalyticallyvia the enzyme retinol dehydratase.This member of the sulfotransferase family is responsible for thecatalytic conversion of retinol into anhydroretinol.¹⁷² In this reaction, a sulfo moiety is first transferred from3′-phosphoadenosyl-5′-phosphosulfate (PAPS) onto theretinol hydroxyl group to produce retinyl sulfate. Sulfate then readilydissociates, generating a resonance-stabilized carbocation that isquenched by proton loss from carbon 4 of the ionone ring to yieldanhydroretinol¹⁷² (Figure8).

3.3. Chemical/photochemical isomerization of retinoids

Spectroscopic properties of retinoids can be directly related totheir conjugated double bond system. Mobile π electrons of polyenesare delocalized over the entire molecule, resulting in resonance stabilizationof the compound.¹⁷³ Thus, polyene singlebonds display some double-bond characteristics contributing to theirpreferred planar conformation. The most stable conformation for retinoidsisall-trans.^174,175 Alternative geometricalisomers introduce some steric hindrance that increases the conformationalenergy compared to theall-trans isomer.¹⁷⁶ Although some retinal isomers introduce onlymild steric clashes, e.g. between 12H and 15H in 13-cis or between 8H and 11H in the 9-cis conformation,other isomers such as 11-cis and 7-cis constitute examples of severely hindered isoprenoids in which theplanar conformation of the polyene chain cannot be sustained.¹⁷⁴ To eliminate the strain, a twist is introducedthat further contributes to the increased conformational energy ofthe retinoid.¹⁷⁷

Cis/trans isomerization of retinals does not occur efficiently in the darkat room temperature. However, an equilibrium between retinoid isomerscan be introduced chemically or photochemically (Figure9). The radical-mediated, iodine-catalyzed isomerization ofpolyenes is a three-step process that involves binding of an iodineatom to a carbon, an internal rotation, and then detachment of theiodine.^178,179 Because iodine atoms are easily formed thermallyfrom I₂, retinoid isomerization can be studied independentlyof light. Starting fromall-trans-retinal, the compositionof retinal isomers at equilibrium was consistent among multiple reportsthat includedall-trans, 13-cis,9-cis, 11-cis, and 9,13-di-cis isomers in ratios of about 0.62, 0.23, 0.11, 0.001,and 0.04, respectively.^177,180,181 The same results were obtained whenall-trans-retinolor its palmitoyl ester was used as the starting material.¹⁸¹ Interestingly, kinetic studies revealed thatthe 9,13-di-cis isomer was a favored intermediatein the isomerization of 9-cis-retinal, whereas 13-cis-retinal was directly converted into theall-trans conformation without the contribution of any other isomeric intermediates.¹⁸¹ Consequently, different isomers lead to a diverseretinoid composition in the equilibrium state. Nevertheless, 11-cis-retinal was never preferably formed upon I₂ or acid-catalyzed isomerization. In contrast, early work by Waldindicated that photolysis of dilute ethanolic solutions ofall-trans-retinal resulted in the formation of about 50%cis-retinals, with an exceptionally high contribution of11-cis-retinal representing 25% of the mixture.^182−184 Since then, quantum yields fortrans/cis andcis/trans photoisomerization upon light excitation of retinalhave been studied under a variety of conditions demonstrating bothisomer and solvent dependence. The quantum yields forall-trans-retinal were considerably lower in polar (0.1–0.2) than innonpolar (0.4–0.7) solvents.^185−189

The influence of solvents on the efficiency and compositionofisomers at photoequilibrium has been attributed to solvent-dependentshifting of the nπ* and ππ* excited states.^190−192 For example, in hexane light illumination led to almost exclusiveformation of the 13-cis isomer whereas increasedsolvent polarity contributed to efficient production of 11-cis, 9-cis, and 7-cis-retinalsin 0.19, 0.06, and 0.005 ratios, respectively.^192,193 Many studies were dedicated to elucidate the mechanism(s) of photoisomerization,particularly the potential role of singlet and triplet excitationstates of retinals that could provide a mechanistic explanation forearly stages of rhodopsin-mediated visual excitation.^{186,190,194−196} Although the directly formed singlet excited state had a major rolein the photoisomerization of eitherall-trans or13-cis-retinal, in the case of 11-cis-retinal and 7-cis-retinal, isomerization occurredalso after an intersystem crossing to an excited triplet state, sothe triplet state was responsible for up to 50% of the observed isomerizationwith the other half of isomerized retinoid arising from the singletstate.^{188,193,197,198} Because the triplet state of chromophore bound torhodopsin has never been spectroscopically observed, it is not clearwhether these observations can be translated into a biologically relevantmodel. Nevertheless, these early studies on retinoid isomerizationclearly showed that the mixture of isomers obtained by any of theavailable methods did not recapitulate the equilibrium observed inliving tissue. Thus, they indirectly facilitated a shift in researchfocus toward the potential role of enzymes and specific binding proteinsin maintaining the composition of retinoid isomersin vivo.

3.4. Dihydroretinol

As mentioned above,retinoid isomers can be directed toward equilibrium by free radicalsvia addition–elimination processes which implicatetransient disintegration of the double bond prior to an internal rotation.^178,181 By analogy, reduction of a selected double bond that allows freerotation followed by its desaturation could represent an alternativeroute to polyene isomerization (Figure10).Although the conjugated double bond system of retinoids is resistantto chemical reduction, this scenario can be effectively completedin vivo.¹⁹⁹ Cyanobacterial andplant CrtIso catalyze the isomerization of (7Z,9Z,9′Z,7′Z)-tetra-cis-lycopene (prolycopene) toall-trans-lycopene.^200−203 This enzyme-mediated isomerization employing redox cofactors occursthrough a reversible saturation–desaturation reaction of thecis-double bonds.²⁰⁴ Animal homologuesof the plant enzyme are inactive toward prolycopene.^125,205 Instead, the mouse CrtIso-related enzyme acceptsall-trans-retinol as a substrate in carrying out the saturation of the retinoid13–14 double bond.^125,206 However, in contrastto plant CrtIso, this reaction is not accompanied by isomerizationof the retinoid, yielding (R)-all-trans-13,14-dihydroretinolas a final product (Figure11).²⁰⁶ Consequently, this animal enzyme has been namedretinol saturase or RetSat.¹²⁵ The enzymaticactivity of RetSat does not contribute to visual chromophore regenerationin the eye but rather influences processes involvingperoxisomeproliferator-activated receptor γ (PPARγ) activity,which regulates lipid accumulation in mice.^125,207,208

4.1. Structure of the Mammalian Retina

The vertebrateeye evolved to utilize key optical principles alongwith the physicochemical properties of retinoids. First, light isfocused by passing through two proteinaceous biological lenses atthe front of the eye, namely the cornea and lens.²⁴² Then the focused wave of photons is absorbed by photoreceptorsof the retina (Figure13), a highly layeredtissue, where rod and cone photoreceptors constitute more than 75%of the cells. Detailed phylogenetic analyses across species demonstratedthat the last common ancestor of all jawed vertebrates evolved ∼400million years ago with a key role for transcriptional master regulatorpaired box gene 6 (PAX6) in controlling development of eyes and othersensory organs.^243−245 Vision is initiated by absorption of lightby photoreceptors, with rod cells acting as photon counters becauseunder dim illumination they can respond to a single photon.^246,247 The extreme photosensitivity of the 11-cis-retinylidenechromophore is modulated by the chemical environment of the opsinchromophore binding pocket, yielding different visual pigments thatrespond maximally to light at different wavelengths, causing the so-called“opsin shift” that allows us to discern differencesin color.^235,248 Forced twisting of the polyenebackbone away from its normally planar configuration induced by thebinding pocket as well as the electrostatic environment surroundingthe chromophore are major factors that influence its absorbance maximum.²⁴⁹ The key role of binding pocket electrostaticsin spectral tuning of the retinylidene chromophore has been vividlydemonstrated in a rationally engineered cellular retinol-binding protein(CRBP).²⁵⁰

There are similarities and differences between rods and cones.Rod cells are more light-sensitive than cones but saturate at relativelylow levels of light. At the light level at which rods reach saturation,cones generate measurable responses but have an extremely high photonsaturation threshold.²⁴² The number andtypes of cones that collect photons in ambient light differ dramatically,from less than 1% in rats to more than 95% in the ground squirrel.^251,252 Both rod and cone cells feature the same structural design. Themost distal portions, called rod/cone outer segments (ROS/COS), arein close contact with the RPE cell layer. These ciliary structuresconnect with the somavia an inner segment endowedwith a high density of mitochondria that supply energy to the highlymetabolically active photoreceptor. The soma in turn connects withsynaptic terminivia inner fibers (Figure13). The specialized photoreceptor cilia containvisual pigments responsible for absorption of light and house allphototransduction proteins needed for amplification and quenchingof the light signal. Here there is yet another difference betweenrods and cones. ROS are made up of a stack of individualized diskssurrounded by the ROS plasma membrane, whereas COS differ by havinga series of invaginations continuously connected with the COS plasmamembrane.

The structure of ROS is better known than that ofCOS because moreadvanced methods were developed for its isolation,^253,254 including mouse ROS, which can be altered genetically.^255−258 ROS structure has recently been reviewed.⁶⁶ In short, a mouse ROS with a length of ∼24 μm and adiameter of ∼1.2 μm²⁵⁹ containsabout 600–800 membranous stacked disks which increase the densityof rhodopsin available for photon absorption. ROS extend up to theapical part of the RPE and are tightly enveloped by microvilli ofRPE cells that increase the contact area of these two cell types tofacilitate transfer of substances, including retinoids.

4.2. Structure of the RPE

Without RPEcells, our vision would not be sustainable. The RPE is a monolayerof highly polarized, quasi-hexagonal, epithelial cells. The apicalmembrane of RPE cells lies adjacent to the photoreceptor OS, whereasthe RPE cell basal surface faces Bruch’s membrane.^260−262 Contact with ROS is maintained by a highly elaborate network ofmicrovilli visible under the electron microscope (Figure14) which in some species changes shape and elongateswhen the eye is exposed to light. About 20–40 photoreceptorcells project toward a single RPE cell. In humans, this ratio dependson the location of these cells in the eye because the gradient ofrod/cone cells and also slight differences in the dimension of photoreceptorsdictates their packing density. In the periphery, the rod to RPE cellratio is 29 whereas, in the fovea, the cones to RPE cells ratio is22.²⁶³ Functions of the RPE cell layerare diverse,^59,264 but from the perspective ofthis review, two roles are the most critical.

The first function of the RPE is to facilitate photoreceptorcellrenewal. To provide optimal signal amplification, membranes of ROSand COS contain high levels of unsaturated lipids.²⁶⁵ These lipids are prone to oxidation in the presence oflight, (photo)reactive retinal, and high oxygen tension,^266,267 which are physiological conditions encountered in the retina. Photochemicalreactions induced by light in transparent retinal tissue require adelicate balance between protein, lipid, and metabolite renewal anddamaged component disposal, which when disturbed can lead to rapidand massive retinal degeneration. Impressively, postmitotic rod andcone photoreceptor cells undergo a daily regeneration process wherein∼10% of their OS volume is shed, subsequently phagocytosedby adjacent RPE cells²⁶⁸ and replaced withnewly formed outer segments. Thus, RPE cells dispose of but also accumulatean immense amount of oxidized cellular debris. Indeed it was estimatedthat each RPE cell phagocytoses hundreds of thousands of OS disksover a human lifetime.²⁶⁹ Several potentiallytoxic byproducts are condensation compounds derived fromall-trans-retinal.^69,270 Dysfunction of such processesas phagocytosis, lysosomal degradation, and removal of waste productsby the RPE can lead to severe retinopathies, including age-relatedmacular degeneration (AMD).^270−274

As a second major function, the RPE expresses key metabolicenzymesrequired for production of the visual chromophore, 11-cis-retinal, and thus comprises an integral part of the retinoid cycle.^{59,63−65,68,69,71−78,80,81,83,85,261,275−281} In the first step of this metabolic pathway, LRAT, through its abilityto catalyze the formation of retinyl esters that are readily sequesteredby aggregation into lipid droplets called retinosomes, changes themass action ratio to favor retinoid uptake from both photoreceptorsand the choroidal circulation.^278,282,283 In addition to LRAT, another critical enzyme called RPE65 (retinoidisomerase) catalyzes the conversion ofall-trans-retinylesters into 11-cis-retinol. Thiscis-retinol is oxidized and sent back to ROS/COS to re-form photoactivevisual pigments. Diffusion likely suffices for this process becausethe chromophore forms, especially in rods, a highly stable covalentcomplex with opsin, thereby driving the transfer of retinoids to photoreceptors.

5.1. CanonicalRetinoid (Visual) Cycle

The initial discovery of a light-sensitivepigment in the retinais generally attributed to a German physiologist by the name of Böll,who, in ca. 1876, observed the “purple red color of the bacillary(i.e. rod) layer of the retina” while dissectingthe retina of a frog kept in the dark just prior to the procedure.^1,294 The red color of frog rod cells had actually been noted some 25years earlier by Müller, who incidentally first described retinalMüller cells,²⁹⁵ but the color wasattributed to hemoglobin and not further explored.¹ Böll made the key observation that the red hue ofthe retina was fleeting, gradually transforming to a yellow colorand then fading over the course of several seconds, leaving the tissuecolorless. Böll insightfully inferred that this light-inducedbleaching of the retina must be reversed when the animal was maintainedin the dark.

A second German physiologist by the name of Kühnegreatly expanded on Böll’s research by showing thata photobleached retina regained its red color when placed in contactwith the RPE and stored in the dark.^296,297 This criticalexperiment demonstrated that at least two different tissues were requiredfor the bleach–regeneration cycle proposed by Böll.Kühne used bile salts, which he had on hand from his experimentson digestion, to solubilize the red pigment and then used the preparationto demonstrate a correspondence between its absorption spectrum andthe spectral sensitivity of the retina to light, firmly establishingthe red substance as the visual pigment of rod cells. Kühnenamed the pigment “sehpurpur” or “visual purple”and later referred to it as “rhodopsin”.²⁹⁷

Despite the rapid progress made by Bölland Kühneon the mechanism of light perception, the field was essentially dormantfor the next 50 years. In the 1930s the task of identifying the molecularcomponents of the visual system was taken up by Wald and his colleagues.Among his many achievements, Wald discovered that the chromophoreimparting a red color to rhodopsin was a vitamin A-derived compoundcalled 11-cis-retinal. Moreover, he found photonsstriking this chromophore could induce a change in its configurationfrom an 11-cis, through a series of photointermediates,to anall-trans state, and that this photochemicalreaction, which initiates the series of retinal color changes observedby Böll and Kühne, represents the first step in thesensing of light by the eye.⁶ He also showedthat, following photoactivation, rhodopsin decomposes into its proteinand retinal components. Wald was the first to lay out a general schemeof chemical reactions, termed the visual or retinoid cycle, whichunderlies visual perception and regeneration.⁶ Dowling, a student of Wald, through detailed measurements of retinoidflow between photoreceptors and RPE during light exposure and darkadaption, established that the retinal liberated from photooactivatedrhodopsin is rapidly taken up by the RPE and esterified. During darkadaption, the flow of retinoids proceeds in a reverse manner fromthe RPE to photoreceptors for rhodopsin regeneration to occur. Thesefindings firmly established the role of the RPE in visual chromophoreregeneration.²⁹⁸ This visual cycle schemewas refined over the years, and the enzymes responsible for catalyzingthe individual reactions were identified. Our current understandingof the retinoid (visual) cycle is summarized in Figure15.

5.2. Cone Visual Cycle

In addition tothe canonical visual cycle, several lines of evidence indicate thatcone photoreceptors might have access to a special source of visualchromophore not available to rods⁸⁵ (Figure16). For example, after equal levels of bleaching,cones dark-adapt faster than rods by a factor of ∼10.²⁹⁹ In contrast to rods, cones operate in brightlight without saturating, implying that the rate of visual chromophoredelivery to these two cell types must be substantially different.^300,301 Additionally, studies have found that the canonical visual cycleis too slow to provide enough visual chromophore to maintain conelight responsiveness under bright light conditions.³⁰² The distribution of retinoids in cone-dominant retinasis substantially different from that of rod-dominant species, withan abundance of 11-cis-retinyl esters found in theretina as opposed to the stores ofall-trans-retinylesters in the RPE.^303,304 Three enzymatic activities,namely isomerase, 11-cis- andall-trans-retinyl ester synthase, and retinol dehydrogenase/reductase, areassociated with membrane fractions from chicken neural retina.³⁰² Cultured primary Müller cells from chickenswere found to convertall-trans-retinol added tothe media into 11-cis-retinol and 11-cis-retinyl esters, suggesting that this cell type could be a site ofvisual chromophore productionin vivo.³⁰⁵ Moreover, the 11-cis-retinol-bindingprotein, cellular retinaldehyde-binding protein (CRALBP), is knownto be expressed in Müller cells, providing additional supportfor the above hypothesis.^306,307 Although significantprogress has been made in elucidating this alternative pathway, mostof the responsible enzymes have not yet been molecularly characterized.A candidate protein responsible for the alternative retinoid isomerization(all-trans-retinol to 11-cis-retinol)activity found in chicken retinas was identified as dihydroceramidedesaturase-1 (DES-1), a member of the integral membrane hydroxylase/desaturaseenzyme family that contains an eight-His-coordinated di-iron activesite.^308,309 This enzyme is a sphingolipid Δ4-desaturasethat converts dihydroceramide into ceramide, with the latter beinga more active signaling molecule.^310,311 Interestingly,DES-1 produces mainly 9-cis- and 13-cis-retinoids rather than 11-cis-retinoids fromall-trans-retinol, which is unexpected given the abundanceof 11-cis-retinoids in the chicken retina.³⁰⁸ Further research is required to determine thephysiological relevance of DES-1 to the synthesis of a visual chromophore.

5.3. Retinoid-ContainingStructures: Retinosomesand Retinal Condensation Products Found in Healthy and Diseased EyesImaged by Two-Photon Microscopy (TPM)

Once released fromROS,all-trans-retinal is reduced toall-trans-retinol which then diffuses into the RPE. There, this alcohol isesterified by fatty acid in a reaction catalyzed by LRAT. As highlyhydrophobic substances, in part because of the physicochemical propertiesof their long fatty acid esters, these retinoid ester products thencoalesce into lipid droplets termed retinosomes, which are found invertebrate RPE.²⁹¹ These esters can beminor or major components of lipid droplets that along with phospholipidstotal about 160 molecular species including other fatty acid esters,triglycerides, cholesterol, cholesterol esters, and various proteins.³¹² Retinosomes are reminiscent of lipid dropletsin other tissues that store other hydrophobic substances. The highlyefficient enzymatic activity of LRAT traps retinol delivered fromthe photoreceptors or from the circulation, whereas retinosomes areabsent in the eyes ofLrat^–/– mice deficient in retinyl ester synthesis. The lipid corecontent of retinosomes appears to be homogeneous.³¹² Retinosomes recruit proteins such as caveolin-1, perilipinsPLIN1-3, sterol carrier protein-2, structural proteins, chaperoneproteins, and redox enzymes.^290,312 We postulated thatretinosomes in RPE cells perform functions similar to those of lipiddroplets in other types of cells, suggesting that they are ratherdynamic tissue-specific organelles that change their composition inresponse to fatty acid, cholesterol, andall-trans-retinol availability. Because retinoids are naturally fluorescent,the study of retinosomes could provide important insights into theformation and metabolism of lipid droplets in general, especiallybecause these structures are accessible for real time TPM imagingin vivo.^{282,289,291,313}

Capitalizing on the intrinsicfluorescence ofall-trans-retinyl esters, noninvasiveTPM revealed that retinosomes are elongated structures approximately8 μm long and 1 μm wide with their long axis orientedperpendicularly to the RPE basal surface (Figure17).²⁹¹ Retinyl esters in retinosomesaccumulate inRpe65^–/– mice lacking retinoid enzymatic isomerization. Retinosomesare located close to the RPE plasma membrane and are essential componentsfor 11-cis-retinal production.^282,312,313

The RPE also accumulates other retinoids, includingretinal condensationproducts.^314,315 These metabolites also can bedetected by TPM, and since they are characterized by unique spectralproperties, the intracellular accumulation and distribution of thesecompounds can be monitored independently from other retinoids (Figure17).³¹³ Resulting frominadequate reduction/clearance ofall-trans-retinal,they are often detected as small 1 μm deposits scattered throughoutRPE cells. These condensation products accumulate most prominentlyin mice lacking the ABCA4 transporter and retinol dehydrogenase 8(RDH8) (Figure17).³¹³ They also increase with age because they are delivered from photoreceptors(at least the first steps of condensation reaction occur in ROS) bydaily phagocytosis.^270,314 Some investigators considerthese retinoid condensation products as major contributors to retinaldysfunction in Stargardt and age-related macular degeneration (AMD)diseases.^270,316,317 Others propose that these biomarkers are merely indicative of inadequateclearance ofall-trans-retinal, which at elevatedlevels may contribute to photoreceptor/RPE degeneration.^318−320

6.1. Rhodopsin

At the center stage ofphototransduction is rhodopsin, the most extensively studied GPCR.Rhodopsin is the main component of disk and plasma membranes of ROS,accounting for 90 and 75% of their protein content. In disk membranes,the density of rhodopsin translates into about 50% of the entire volumeor surface area.^{61,66,79,225,226,235,321−324} Thus, it is not surprising that the expression level of rhodopsindictates the size of the ROS.^{259,325−327} Although rhodopsin is not uniformly distributed throughout disks,^84,328 its local high density within each disk allows efficient absorptionof light. Corresponding visual pigments in cone cells of frog retinaare so dense that they form crystalline structures.³²⁹ Physiologically, the minimal building block of rhodopsinis a dimer in which only one monomer is activated under normal lightingconditions^330−335 (reviewed in refs (336−338)).

The fundamental photochemical reaction of our visual systemis isomerization of 11-cis-retinylidene toall-trans-retinylidene (Figure18). The Schiff base between 11-cis-retinal and Lys296of opsin is protonated to allow a spectral shift to longer wavelengths(at least in rhodopsin, green and blue pigments). It is remarkablethat a ligand, retinal, which is just slightly larger than tryptophan,when photoisomerized causes a reliable change in the conformationof rhodopsin to its activated form that couples with G protein. Thisactivation is accomplished through geometriccis/trans isomerization of the chromophore,¹⁸² deprotonationof the Schiff linkage,³³⁹ and reorganizationof water molecules within the TMD of this receptor.^{333,340−342}

Photoactivation of rhodopsin causesconformational changes thatprovide a binding site for the rod G protein called transducin.^343,344 No high resolution structure of the complex is yet available, butlower resolution methods have been informative. On the basis of structuralmass spectrometry techniques, we found that the transition of groundstate rhodopsin to its photoactivated state causes a structural relaxationthat then tightens upon transducin binding.³³³ Using affinity chromatography, we trapped and purified the photoactivatedrhodopsin–transducin complex. Scanning transmission electronmicroscopy demonstrated about a 221 kDa molecular weight for thiscomplex. A 22 Å structure was calculated from projections ofnegatively stained photoactivated rhodopsin–transducin complexes.The determined molecular envelope accommodated two rhodopsin moleculestogether with one transducin heterotrimer, indicating a heteropentamericstructure for the photoactivated rhodopsin–transducin complex.³³⁴ The dimeric structure of rhodopsin in the complexwas confirmed using succinylated concanavalin A as a labeling probe.³⁴⁵ Recently, we used the retinoid chromophores,11-cis-retinal, 9-cis-retinal, andall-trans-retinal to monitor each dimeric rhodopsin monomerwithin a stable complex with transducin. We found that each of thedimeric rhodopsin monomers contributed differently to the pentamericcomplex, indicating a functional distinction between rhodopsin monomersin their oligomeric form.³³² For a moredetailed description of the activation events, recent reviews areavailable (refs (66,79, and346−349)).

Two other importantquestions need to be answered about the rhodopsincycle. First, how is the chromophore released and how do opsins recombinewith 11-cis-retinal to regenerate rhodopsin and conevisual pigments? Mechanistically, more information is available forrhodopsin than for cone pigments. Key residues in rhodopsin’sactive site are Lys296, Glu113, and Glu181 (Figure19).^{60,139,226,227,240,350−355} The 11-cis-retinylidene bond is protonated, andGlu113 is the counterion of this linkage. A counterion is essential,as positively charged groups are extremely rare in the TMD of membraneproteins. Upon illumination of rhodopsin (λ_max =500 nm), the chromophore undergoes geometrical isomerization.^356,357 Next, rapidly formed and decaying intermediates have been detectedbefore Meta I is observed (λ_max = 478 nm). Thoughthe difference in absorption results from relaxation of the chromophore,only small changes in the protein moiety take place at this stage^358−360 and it is believed that a switch in the counterion occurs from Glu113to Glu181.^{324,361−364} Further relaxation combined with Schiff base deprotonation resultsin a signaling form called Meta II (λ_max = 382 nm)³⁴³ which then interacts with G protein-coupledreceptor kinase 1 and arrestin.^{60,62,239,365,366} Especially in cold blooded vertebrates, a prominent fraction ofMeta I relaxes into Meta III (λ_max = 465 nm), thedifference in the latter’s light absorption derived from ananti tosyn thermal isomerization of theSchiff base double bond.³⁶⁷ From both MetaII and Meta III, a protonated carbinol ammonium ion is formed beforeall-trans-retinal is released from opsin. When regenerationwith 11-cis-retinal subsequently occurs, formationof the Schiff base requires polarization of the carbonyl group of11-cis-retinal and deprotonation of the Lys296 sidechain amine as well as exclusion of water from the active site (Figure19). Regeneration and recombination of 11-cis-retinal with opsin restores the dark state conditionneeded for subsequent photon absorption. Although there is convincingevidence for the roles proposed for Glu113 and Glu181, independentverification of this switch and the whole mechanism of chromophoreregeneration is still lacking.

How the chromophore migrates into and out of opsinremains an openquestion. Taking into account the hydrophobic nature of retinal, doesit dissociate into the lipid bilayer or the cytoplasm for the reductionreaction, or could it enter the intradiscal space where condensationproducts of retinal start forming? Similar to other GPCRs, which inaddition to orthosteric-binding sites contain other well-defined allostericligand-binding sites, rhodopsin also has two other retinoid-bindingsites within opsin^368,369 in addition to the retinylidenepocket (site 1). Site II is called an entrance site, and the exitsite (site III) is occupied by retinal after its release from siteI. The crystal structure of opsin,³⁷⁰ anopsin structure with another retinoid bound,³⁷¹ and mutagenesis studies³⁷² all suggestan escape and entrance route for retinal.

6.2. RetinolDehydrogenases (RDH’s)

An integral part of the retinoidcycle is the interconversion ofretinals and retinols.^64,287 Enzymes that catalyze this processcan be classified into three major protein families: cytosolic alcoholdehydrogenases (ADH’s) that belong to a medium-chain dehydrogenase/reductasefamily and selected members of the aldo–keto reductase family(AKR’s)³⁷³ and microsomal RDH’sthat represent the short-chain dehydrogenase/reductase (SDR) group.³⁷⁴ However, only RDH’s contribute to vision-relatedmetabolism of retinoids.²⁸⁷ The universalredox carriers for these reactions are the dinucleotide cofactorsNAD(H) and NADP(H). In ADH’s and RDH’s they are boundby a Rossmann fold, a classic structural element composed of 6 to7 parallel β-strands flanked by 3–4 α-helices presentin these enzymes (Figure20).³⁷⁵ This structural motif contains a Gly-rich sequence (TGXXXGXG)responsible for its structural integrity and binding of the diphosphateportion of the nucleotide cofactors. An acidic residue binding tothe 2′ and 3′ hydroxyls of the adenine ribose and locateddownstream of the Gly-rich motif confers NAD(H) specificity, whereasNADP(H) binding is dictated by the presence of a basic residue withinthe Gly-rich segment.³⁷⁵ By contrast, AKR’sdo not contain the canonical Rossmann fold. Preferable NADPH bindingoccurs within the characteristic (β/α)₈ motifof this protein family.³⁷⁶ Despite theirconserved mode of cofactor binding, ADH and RDH families of oxidoreductasesreveal diverse protein domain architectures and mechanisms of catalysis.ADH’s depend on a catalytic Zn atom bound in the active site,which electrostatically stabilizes the substrate’s oxygen andthus increases the acidity of the alcohol proton.³⁷⁷ In contrast, SDR’s show a Tyr-based catalytic centerwith adjacent Ser and Lys residues.^378−381 Here, the deprotonated phenolicgroup of Tyr initially forms a hydrogen bond with the alcohol hydroxylgroup and the deprotonated Tyr residue acts as a catalytic base toextract a proton from the substrate’s hydroxyl group. The hydrideion, extracted from the substrate, can be directly transferred toposition 4 of the nicotinamide ring. In addition to the interactionwith the nicotinamide ring of the cofactor, the reaction intermediateis stabilized by the hydroxyl group of an adjacent serine residue(Figure20).³⁸² Becausethe phenolic group of the Tyr side chain has a pK_a value around 10, the ε-amino group of Lys is neededto convert tyrosine to tyrosinate (pK_a 7.6), to facilitate catalysis at neutral pH. Additionally, a Lysresidue forms hydrogen bonds to both the 2′- and the 3′-hydroxylgroups of the cofactor’s ribose moiety and thus enforces aproper orientation of the nicotinamide ring to allow a pro-S hydride transfer only. Recently, an Asn residue was shownto stabilize the position of this catalytic Lysvia a conserved water molecule. Thus, the final sequence of the catalytictetrad of SDR’s is composed of Asn, Ser, Tyr, and Lys residues(Figure21).³⁸³ Thecatalytic mechanism of AKR’s, in principle, is similar to thatfound in SDR’s with an active site Tyr residue and an assistingLys residue facilitating the deprotonation of the Tyr hydroxyl group.³⁸⁴

The RDH’s represent a microsomal SDR group with anoverallsequence similarity of at least 30% (Figure21) although the catalytic core of these enzymes reveals a much higherhomology with nearly identical folding. Despite these similarities,the mode of membrane binding and membrane topology of specific RDH’sis a matter of controversy. Based on biochemical studies, RDH1 isanchored in ER membranes with the catalytic domain facing the cytoplasm.³⁸⁵ The N-terminal residues are essential for themembrane localization and topology of this enzyme, whereas the C-terminuswas postulated to be involved in stabilization of the protein’smembrane orientation.³⁸⁵ In contrast tothis model, RDH12 was reported to be a glycoprotein carrying an endoglycosidaseH-sensitive sugar modification, which suggests a luminal orientationof this enzyme.³⁸⁶ Yet other models indicatethat the hydrophobic stretch of the catalytic domain in RDH1 and RDH4can contribute to membrane binding.^387,388 An interestingcase is RDH8, which localizes to ROS/COS. Efficient transport to theROS/COS is mediated by a signaling sequence at the C-terminus of thisenzyme whereas membrane anchoring is achieved by fatty acylation ofconserved Cys residues.³⁸⁹

Althoughall RDH’s identified in vertebrates can utilizeretinol or retinal, some have wide substrate specificities, and retinoidsare not their preferred physiological substrates.^374,390 For example, RDH1, RDH3, RDH4, RDH6, and RDH7 reveal 25–60times higher affinities for androgens thanall-trans-retinol.^391−393 In fact only RDH5, RDH8, RDH10, RDH11, RDH12,RDH13, RDH14, and retSDR1 were proven to be expressed in the retinaor RPE, and their roles have been studied in the context of the visual(retinoid) cycle.^68,287 Based on their preferred substrategeometry and role in the retinoid cycle, this group of enzymes canbe classified intoall-trans and 11-cis-retinol dehydrogenases. RDH8 and RDH12 belong to the first class,whereas RDH5, RDH11, and RDH10 act on 11-cis-retinoids.Functions of the two remaining enzymes, RDH13 and RDH14, have yetto be adequately assigned.³⁹⁴ Reactionscatalyzed by RDH’s are fully reversible. In a test tube, thenet direction of retinoid interconversion depends on the oxidationstate of the provided cofactor and the ratio between the concentrationsof substrate and product. However, in more complexin vivo systems, the direction of the enzymatic reaction is determined byenzyme specificity for binding either NAD(H) or NADP(H). Under physiologicalconditions the ratio between NAD/NADH is close to 1000;²⁸⁷ thus, RDH’s that bind this cofactorcan contribute significantly only to retinol oxidation. In contrast,the ratio of NADP to its reduced form is about 0.005,³⁹⁵ such that enzymes utilizing this dinucleotidereduce retinal to retinol.

The physiological role and significanceof particular RDH’sin vitamin A homeostasis, retinoic acid signaling, and visual chromophoreregeneration has recently been extensively reviewed^68,287,396 and thus will not be describedhere. However, it is worth noting that, in addition to genetic andbiochemical identification of RDH’s, many of these enzymeswere characterizedin vivo in the past few years.^397−400 These studies not only provided detailed information about the physiologicalfunction of many RDH’s but also led to the development of animalmodels to investigate their roles in human pathological conditions,including retinal degenerative diseases.⁴⁰¹

6.3. Lecithin/Retinol Acyl Transferase (LRAT)

LRAT is the main enzyme that catalyzes retinyl ester formationin most tissues,^147,402,403 with the exception being adipocytes that instead exhibit acyl-CoA-dependenttransferase activity of a protein (acyl-CoA:retinol acyltransferaseor ARAT) yet to be identified.⁴⁰⁴ Consequently,LRAT is critical for uptake and storage of retinoids in peripheraltissues, including RPE cells where it plays a pivotal role in providingsubstrate for visual chromophore regenerationvia the enzymatic activity of RPE65.^147,148,405

Localized in the endoplasmic reticulum (ER),LRAT is a 25 kDa bitopic integral membrane protein with a single membrane-spanninghelix localized at the C-terminus⁴⁰⁶ anda potential membrane-interacting N-terminal domain.⁴⁰⁷ The C-terminal domain is critical for post-translationaltargeting of the enzyme to the endoplasmic reticulum (ER) in a cytosolicTMD recognition complex-dependent manner.^406,408 On the basis of its amino acid sequence and predicted tertiary structure,LRAT is classified as a member of the NlpC/P60 thiol peptidase proteinsuperfamily (Figure22).⁴⁰⁹ Besides LRAT, there are seven genes in the human genomethat encode proteins belonging to the NlpC/P60 family: two neurologicalsensory proteins (NSE1-2) and five H-ras-like tumor suppressors (HRASLS1-5).^409,410 The common feature of LRAT and HRASLS proteins is a 6 amino acidsequence that contains a conserved catalytic Cys residue (NCEHFV).⁴¹¹ Although the structure of LRAThas yet to be determined, recently solved structures of two LRAT-likeproteins, human HRASLS2 and HRASLS3, provide important insights intothe molecular organization of this enzyme.^411,412 By analogy to HRASLS proteins, LRAT’s basic structural motifis largely reminiscent of papain-like proteases and consists of afour-strand antiparallel β-sheet, three α-helices, andconserved catalytic residues Cys161, His60, and His72 that definethe active site located at the N-terminus of helix α3 and β-sheetsβ2 and β3, respectively (Figure22).⁴¹¹ Although the overall folding ofLRAT is similar to that of other NlpC/P60 peptidases, there are significanttopological differences derived from a circular permutation withinthe catalytic domain of classical NlpC/P60 proteins.^409,413 Consequently, alternatives to peptidase activity evolved in LRAT-likeproteins. The best characterized example is the acyltransferase activityof LRAT, which catalyzes the formation of retinyl esters by transferringan acyl group directly from the sn-1 position of phosphatidylcholine(PC) ontoall-trans-retinol.^145,146,414

As a consequence of its structural relationship to thiolpeptidases,LRAT adopts an analogous catalytic strategy whereby the deprotonatedCys161 serves as a nucleophile attacking the carbonyl carbon of anester bond in the lipid substrate, both forcing the carbonyl oxygento accept a pair of electrons and transforming the sp²-hybridized carbon into an sp³-hybridized tetrahedral intermediate (Figure23).^411,415,416 Collapseof this intermediate results in transient acylation of the proteinby formation of a thioester bond at the Cys161 sulfhydryl group. Concomitantly,1-hydroxy-2-acyl-sn-glycero-3-phosphocholine (Lyso-PC)is liberated as a first product of the reaction. Deprotonation ofthe hydroxyl group of retinol then permits decomposition of the thioesterintermediate and transfer of the acyl group from the enzyme onto retinolto form retinyl esters. Several lines of evidence support this LRATmodel. Initially, a role for Cys161 and His60 in catalysis was derivedfrom site-directed mutagenesis studies where replacement of eitherof these two amino acids abolished retinyl ester formation.^417,418 Recently, the proposed mechanism was proved by trapping the catalyticintermediate in the absence of an acyl acceptor and directly detectingthe covalent thioester protein modification by mass spectrometry.⁴¹⁵ An identical enzymatic mechanism holds forother LRAT-like proteins.⁴¹¹ Importantly,despite their highly conserved catalytic domains, HRASLS proteinscannot employall-trans-retinol as an acyl acceptorand they lack specificity toward the sn-1 ester cleavage site as well.⁴¹¹ Instead, they catalyze both lipid hydrolysisand acyl transfer onto a variety of enzyme-specific substrates, suchas lyso-phospholipids or phosphatidylethanolamine (PE).^{411,419−422} These fundamental differences in enzymatic activity do not arisefrom changes in the catalytic mechanism but rather are determinedby subtle modifications in the primary sequence and structure of theseproteins. Despite recent advances in understanding the principlesof catalysis, several critical questions remain, including the evolutionaryand structural basis for adaptation ofall-trans-retinolprocessing by LRAT.

6.4. Acyl-CoA/RetinolAcyltransferase

Early studies concerning the esterificationofall-trans-retinol revealed two independent enzymaticactivities that led toformation of retinyl esters. In addition to lecithin-dependent acyltransfer facilitated by LRAT described above, profound acyl-CoA-dependentactivity has been reported to exist in a variety of tissues, includingsmall intestine, liver, adipocytes, skin, testis, and retina.^423−429 In contrast to LRAT, which efficiently utilizes phospholipids asacyl donors, acyl-CoA/retinol acyltransferase (ARAT) requires a preactivatedacyl moiety coupled to coenzyme A (Figure24).

ARAT has never been purified orcloned. However, studies ofLRAT-deficient mice indicatethat the intestinal absorptionof vitamin A decreased to 50% that of wild type animals challengedwith a physiologic dose of retinol.⁴⁰² Onthe basis of this evidence, ARAT may contribute to retinyl ester formationwithin the intestine and thus facilitate retinoid uptake and packaginginto chylomicrons. A distinct role of acyl-CoA-dependent retinoidesterification has been proposed for the retina. On the basis of enzymaticstudies, retinas isolated from cone-dominant species such as ground-squirreland chicken revealed retinoid isomerase activity that, in contrastto RPE65, convertsall-trans-retinol directly into11-cis-retinol.^302,430 This enzymaticreaction is thermodynamically driven by secondary esterification ofnewly produced 11-cis-retinol in a palmitoyl-CoA-dependentmanner. Studies involving primary cultures of chicken Müllercells indicate that inner retinal ARAT enzymatic activity is associatedwith this cell type.^85,302,431 Interestingly, the retinal ARAT preferably synthesized 11-cis-retinyl esters⁴²⁸ distinguishingit from intestinalall-trans-ARAT and suggestingthe existence of two or more separate enzymes responsible for acyl-CoA-dependentall-trans-retinol esterification. Intestinal acyl-CoA-diacylglycerolacyltransferase 1 (DGAT1) has been shown to catalyze formation ofretinyl esters in an acyl-CoA-dependent mannerin vitro.^402432,433 However,later detailedin vivo studies indicated that DGAT1deficiency did not cause a decline in retinol esterification but rathermarkedly reduced postprandial plasma trigliceride and retinyl esterexcursions by inhibiting chylomicron secretion.⁴³⁴

6.5. Retinoid Isomerase (RPE65)

Our understandingof RPE65 biochemistry has changed dramatically since the lastChemical Reviews article covering the visual cycle.⁴³⁵ Once thought to function solely as a retinoid-bindingprotein, RPE65 has now been conclusively identified as the retinoidisomerase of the canonical retinoid cycle.

7.1. Acyl versusO-Alkyl Cleavagein the Hydrolysis of Esters

The ester cleavage reaction catalyzedby RPE65 is not an ordinary ester bond hydrolysis whereby attack ofwater on the acyl carbon generates a tetrahedral intermediate thatcollapses to form a carboxylic acid and an alcohol (Figure28). Instead, the ester dissociates by cleavage oftheO-alkyl bond. Owing to this distinction, we preferto refer to the process as ester “cleavage” rather than“hydrolysis.” This unusual reaction was identified byusing various isotopically labeled retinols as substrates for theisomerization reaction. It was found that a stereochemical inversionof carbon 15 occurs^477,478 and that the 15-hydroxy oxygenis lost¹⁷¹ and replaced by bulk water-derivedoxygen during the isomerization.⁴⁵² Because11-cis-retinol is thermodynamically less stable thanall-trans-retinol by ∼4 kcal/mol,¹⁸¹ it has been argued that ester cleavage, which typicallyreleases ∼5 kcal/mol of free energy, could be used to drivethe isomerization reaction.⁴⁷⁹ The requirementof CRALBP and other binding proteins for robust 11-cis-retinol production by RPE65 indicates that product release couldbe rate limiting.⁴⁷⁶ The unusual estercleavage reaction instead seems to be more important in overcomingthe ∼36 kcal/mol activation energy barrier of the double bondisomerization.¹⁷¹ The retinoid polyenechain is relatively rigid, owing to favorable continuous π-orbitaloverlap. Thus, in order for isomerization of these double bonds tooccur at physiological temperatures, the carbon–carbon bondorder must be temporarily lowered.

7.2. BinuclearNucleophilic Substitution Mechanismfor Retinoid Hydrolysis/Isomerization

Taking into accountthese biochemical data, three different mechanisms of RPE65-dependentretinoid isomerization have been proposed. The first, proposed byRando and colleagues, involves the attack of an enzyme-associatednucleophile on C11 of the retinyl ester with simultaneous ester dissociationand shuffling of the double bonds (Figure29). The enzyme-linked retinoid intermediate could undergo low-energyrotation around the 11–12 single bond to acis-like conformation. Attack of water or hydroxide on C15 would leadto a reshuffling of the double bonds and dissociation of the retinoid–enzymecovalent intermediate locking the retinoid in an 11-cis configuration. This mechanism, which can be classified as a dualS_N2′ nucleophilic substitution reaction, predictsa high degree of 11-cis-retinol product specificityfor RPE65. However, RPE65 does not exhibit such specificity⁴⁶⁸ and can readily produce 13-cis orall-trans-retinol, depending on the reactionconditions and retinoid-binding proteins used for the assay.⁴⁷⁶ Structurally, RPE65 also does not possess asuitable nucleophile such as a Cys residue in its active site.⁴⁵²

7.3. UnimolecularNucleophilic Substitution Mechanismfor Retinoid Isomerization

A second mechanism, postulatedby Palczewski and colleagues, proposes a key role for a carbocationintermediate in the isomerization reaction (Figure30). In this reaction involving an S_N1′ nucleophilicsubstitution mechanism, ester dissociationvia O-alkylcleavage removes electrons from the polyene, thereby generating aretinylic cation with reduced carbon–carbon bond order allowingbond rotation to take place. Quantum mechanical calculations indicatethat the activation energy oftrans/cis isomerization at the 11–12 bond is reduced to about 18 kcal/mol,consistent with the experimentally determined energy of activation.¹⁷¹ The aromatic residues lining the active sitecavity of RPE65 are ideal for stabilizing carbocation intermediates.⁴⁸⁰ Following rotation of the 11–12 bond,likely under steric influence by the enzyme active site, water orhydroxide attacks C15, quenching the carbocation with the 11–12double bond in acis configuration. The interiorcavity of RPE65 indeed has a curved shape that can accommodatecis retinoid isomers (Figure27).Importantly, this mechanism allows for the generation of alternativeisomers such as the experimentally observed 13-cis-retinol.^171,468 As discussed earlier, retinyliccation formation from retinol or retinyl esters is facilitated byBrønsted or Lewis acids. The iron-coordinated fatty acid observedvia crystallographic and XAS data suggests that the RPE65iron cofactor could promote catalysis by coordinating the ester moietyand facilitating its dissociation.⁴⁵⁵ Thismechanism thus bears substantial similarity to the well-characterizedCarr–Price type reactions described earlier, with the exceptionthat 11-cis-retinol rather than anhydroretinol isgenerated in the RPE65 active site.

7.4. Radical Cation Mechanismfor Retinoid Isomerization

A third mechanism, recently proposedby Redmond and colleagues,posits a role for a retinyl radical cation intermediate in the isomerizationreaction (Figure31). This proposal is basedon the finding that certain radical spin-trap compounds, for exampleN-tert-butyl-α-phenylnitrone (PBN)can inhibit RPE65-mediated isomerization in an uncompetitive manner.^481,482 In this proposal, removal of a single π electron from thepolyene by an unknown electron acceptor generates a retinyl radicalcation intermediate that can undergo double bond rotation to formcis isomers followed by quenching of the radical cationto form an 11-cis-retinyl ester. Ester cleavage thenoccurs to produce 11-cis-retinol. Reversal of theisomerization and ester cleavage steps in relation to the carbocationmechanism was proposed based on the finding thatall-trans-retinyl ester could not easily be accommodated in the RPE65 activesite whereas 11-cis- and 13-cis-retinylesters could.⁴⁶⁷ However, more researchis required to develop the mechanistic details of this scheme.

8.1. Retinoid-BindingProteins Involved in theRetinoid Cycle

The hydrophobic nature of retinoids limitstheir ability to diffuse in aqueous environments. This property presentsa barrier to retinoid transport from storage sites to sites of utilizationas well as between cellular membranes. Retinoid-binding proteins overcomethis barrier by reversibly binding and sequestering retinoids awayfrom water in internal cavities, greatly facilitating their diffusion.A number of retinoid-binding proteins have been characterized.⁴⁹⁴ Here, the discussion focuses on those bindingproteins involved in transport of retinols and retinals.

Whenrequired by the body, vitamin A liberated from its hepatic storagesites in Stellate cells by retinyl ester hydrolysis is complexed witha 21 kDa retinoid-binding protein belonging to the lipocalin familycalled retinol-binding protein 4 (RBP4) to form holo-RBP4.²⁴ The main structural feature of holo-RBP4, determinedcrystallographically in the early 1980s, is an eight-stranded β-barrelcore containing a single retinol-binding site (Figure32).⁴⁹⁵all-trans-Retinol is oriented in the binding pocket with its hydroxyl groupfacing the solvent and the retinyl moiety snuggly bound by a numberof nonpolar residues in a highly complementary fashion, explainingthe high binding specificity toward theall-trans isomer. Holo-RBP4 circulates in the plasma in complex with a secondprotein called transthyretin, which by increasing the molecular weightof the overall complex prevents holo-RBP4 from being excreted in theurine.^24,496

Inside cells, retinol is transported between membranes incomplexwith a second binding protein called cellular retinol-binding protein(CRBP). A member of the intracellular lipid-binding protein family,this compact 15 kDa protein is evolutionarily unrelated to RBP4.⁴⁹⁷ Two isoforms of the protein, CRBP I and CRBPII with ∼50% sequence identity depending on the species, exhibitdifferential tissue expression.⁴⁹⁴ CRBPI is expressed in many tissues, including the eye, whereas CRBP IIexpression is restricted to the intestine. The structure of CRBP,similar to that of RBP4, features a β-barrel fold that housesthe retinoid-binding site.⁴⁹⁵ However,the orientation of retinol in the binding pocket is reversed in relationto that in holo-RBP4 with the β-ionone nearest the mouth ofthe pocket and the hydroxyl group hydrogen bonding with a Glu residueat the base of the cavity. An important role for CRBP inall-trans-retinol trafficking in the retina has been demonstrated inCRBP I^–/– mice, which show defectivetransport ofall-trans-retinol from photoreceptorsto ER membranes of the RPE. This is evidenced by accumulation ofall-trans-retinol in the retina and reduced formation ofretinyl esters in the RPE.⁴⁹⁸

Tworetinoid-binding proteins are specifically expressed in theeye.⁴⁹⁴ The first of these is an intracellular-bindingprotein CRALBP that displays a binding preference for 11-cis-retinoids.⁴⁹⁹ CRALBP is expressed predominantlyin two retinal locations, the RPE and Müller glial cells, whereit plays a key role in visual chromophore regeneration by binding11-cis-retinoids, protecting them from esterificationor from photo- or thermal isomerization and facilitating their intracellulartransport.^476,500,501 11-cis-Retinal and 11-cis-retinolare the main retinoids associated with CRALBP isolated from bovineretina.^499,502 It can also effectively bind 9-cis-retinoids as well but not 13-cis-retinoids.⁵⁰² The gene encoding CRALBP,RLBP1, was cloned in 1988⁵⁰³ and was localizedto human chromosome 15.⁵⁰⁴ CRALBP is oneof the founding members of the CRAL-TRIO protein family, members ofwhich share a common three-dimensional architecture.^505−507 The crystallographic structure of the CRALBP–11-cis-retinal complex has been determined, revealing a curved bindingpocket with high shape complementarity to 9-cis and11-cis retinoid isomers, consistent with its ligand-bindingpreferences.⁵⁰⁷ The binding pocket completelyshields the retinoid from solvent. Bound 11-cis-retinalis found in a 6-s-trans, 11-cis,twisted 12-s-cis configuration. The near perfectcis configuration of the 11–12 double bond imposedby the retinoid-binding pocket is likely important to prevent unwantedphotoisomerization and thermal isomerization. A patch of basic aminoacid residues on the protein’s surface probably mediates theinteraction of the protein with acidic phospholipids, which inducedissociation of the bound retinoid.⁵⁰⁸ Mutationsin the CRALBP gene are associated with several retinal diseases, includingretinitis pigmentosa, Newfoundland rod-cone dystrophy, fundus albipunctatus,and Bothnia retinal dystrophy.⁵⁰⁹

The second eye-specific retinoid-binding protein is a soluble lipoglycoproteincalled interphotoreceptor-binding protein (IRBP). This large, 136kDa protein is produced by photoreceptors and secreted into the interphotoreceptormatrix, where it is the most abundant extracellular protein. Unlikeother binding proteins that contain a single retinoid-binding site,IRBP has at least three high affinity sites. The protein can alsobind several isomeric forms of retinol and retinal but has a preferenceforall-trans and 11-cis-retinoids.^510,511 IRBP can also bind a number of nonretinoid, hydrophobic ligands,but the physiological significance of this capability is not currentlyunderstood.⁵¹² The retinoid-binding preferencesand localization of IRBP indicate that it participates in the retinoidcycle by transporting retinoids between photoreceptors, RPE, and Müllercells. Interestingly, IRBP knockout mice do not exhibit acute problemswith vision or dark adaption, and no human disease has been attributedto mutations in the gene encoding IRBP. The protein consists of fourhomologous “modules” generated by gene duplication.⁵¹² Full-length IRBP, as observed by negative stainelectron microscopy, adopts a rod-shaped structure that is flexibleand undergoes major conformational changes in the presence of retinoids.⁵¹³ The crystal structure of an isolated modulefromX. laevis IRBP has been determined, revealinga two-domain architecture.⁵¹⁴ Domain Aadopts a ββα-spiral fold whereas domain B formsan αβα sandwich. Although a retinoid-bound structurehas not yet been obtained, two candidate-binding sites have been identifiedthrough molecular modeling: one in the hinge region connecting thetwo domains and a second in domain B. Notably, domain B of the IRBPmodule shares structural similarity with the ligand-binding domainof CRALBP.⁸³

8.2. Structureand Function of ATP-Binding CassetteTransporter Member 4 (ABCA4)

The metabolism of vitamin Ain the eye involves a complex interplay between over twenty differentproteins. The flow of retinoid substrates and products between componentsof the cycle depends on specific binding proteins and transporters.The retinal-specific ATP-binding cassette transporter, ABCA4, playsa special role in this process. ABCA4, a member of the ABCA transportersubfamily, is predominantly expressed in the outer segments of photoreceptorcells where it is located in the rims of rod disk membranes and coneincisures.^515−517 As indicated by numerous biochemical studiesand the phenotype ofAbca4^–/– mice, the main function of this transporter is to acceleratethe clearance ofall-trans-retinal from ROS/COS.^{401,518−520}

Human ABCA4 is an integral membraneprotein with 2273 residues that form two homologous but nonidenticalparts. Each carries six membrane-spanning helices that constitutea TMD, a soluble cytoplasmic domain (CD) that hosts a canonical nucleotide-bindingsite (NBD) with Walker A and Walker B motifs characteristic of ATP-processingenzymes, and an exocytoplasmic (intradiscal) domain (ECD) (Figure33).⁷⁶ The overall topologicalmodel for ABCA4 is supported by multiple glycosylation sites identifiedin both ECD domains, whereas CD1 hosts multiple phosphorylation sites.^76,521,522 The structure of native bovineABCA4 has been determined by negative stain electron microscopy toa resolution of 18 Å, revealing the overall shape of the molecule.⁵²³ On the basis of the accepted model of ATP-driventransport across a lipid membrane, binding of a molecule to be transportedincreases the affinity of NBDs for ATP. The nucleotide then inducesa conformational change of NBDs that come in close contact to forma dimer with the two nucleotide molecules positioned at its interface.This movement is translated onto a TMD that induces the translocationof the substrate molecule across the lipid membrane. Such conformationalchanges have indeed been observed by electron microscopy and hydrogen–deuteriumexchange.⁵²³ Subsequent hydrolysis of ATPand dissociation of ADP prompt the separation of NBDs, returning thetransporter to its initial state and completing the cycle. In theabsence of substrate, ABC transporters undergo cycles of slow ATPhydrolysis by individual NBDs, resulting in a basal ATPase activity.Although numerous lipids stimulate ATP hydrolysis by ABCA4,all-trans-retinal or its phosphatidylethanolamine (PE) conjugate,N-retinylidene-PE (N-ret-PE) are the preferredsubstrates.^524,525 The topology of this proteinin combination with the logic of the visual cycle suggest that ABCA4acts as an importer, an assumption recently confirmed experimentally.⁵²⁵ Interestingly, ABCA4 still remains the onlyknown example of an importer among eukaryotic ABC transporters.

The importer activity of ABCA4 has consequences for vitaminA metabolismin photoreceptors (Figure33C). Decay of photoactivatedrhodopsin results in hydrolysis of the opsin-retinylidene Schiff basebond followed by subsequent release ofall-trans-retinalinto the disk membrane.⁸⁴ The next stepin the visual cycle is reduction of newly liberatedall-trans-retinal toall-trans-retinol byall-trans-RDHs (mainly RDH8 in mouse retina), which associate with the cytoplasmicside of the disk bilayer.^64,400 The relatively highhydrophobicity ofall-trans-retinal allows its rapidpartition between the inner and outer leaflets of disk membranes,ensuring its accessibility to RDHs.^526,527 However,the high chemical reactivity of aldehydes also leads to spontaneousformation ofall-trans-retinal adducts with primaryand secondary amines. In the biological membrane environment,all-trans-retinal reacts predominantly with PE to formN-ret-PE that, similar to phospholipids, cannot freely flipbetween the inner and outer leaflets of the lipid bilayer. In a testtube, the formation of N-ret-PE in a mixture of chloroform/methanol(2:1) occurs with a bimolecular rate constant of about 3.75 ×10^–2 M^–1 s^–1 while the rate of its hydrolysis is about 7.9 × 10^–6 s^–1.⁵²⁸ This reversible reaction is highly dependent on the presenceof water. The time scale for this processin vivo remains to be elucidated. Upon a 45% bleach of rhodopsin in wild-typemice, about 24% of releasedall-trans-retinal wasdetected in the form of a conjugate with PE.⁵²⁹ Thus, the main role of ABCA4 could be aiding the movement ofN-ret-PE to the cytoplasmic side of disk membranes. Becausethe Schiff base bond inN-ret-PE is susceptible tohydrolysis, the resultingall-trans-retinal eventuallycan be metabolized toall-trans-retinol. Taking intoaccount the partition of retinals into the lipid bilayer and a relativelyslow rate of ATP hydrolysis by ABCA4 equivalent to three enzymaticcycles per second, one can assume that only a fraction of the totalall-trans-retinal is processed by ABCA4.⁵³⁰ Nevertheless, the activity of ABCA4 turns out to be essentialfor loweringall-trans-retinal concentrations belowthe threshold that could cause photoreceptor toxicity.⁴⁰¹

8.3. Condensation Reactionsof Retinal

Delayed clearance ofall-trans-retinal from thephotoreceptors after light exposure can have dramatic pathophysiologicalconsequences. In cultured ARPE-19 cells derived from human RPE cells,exposure to 10 μMall-trans-retinal causedprofound cytotoxicity after less than 1 min of incubation by inducinga Ca²⁺-driven apoptotic cell death pathway.³¹⁸ Because rhodopsin concentration in ROS reaches4 mM,²⁵⁷ bleaching of just 0.5% of thetotal amount could potentially generate toxic levels ofall-trans-retinal if this retinoid is not efficiently removed from the retina.The mechanism ofall-trans-retinal toxicity involvesthe generation of superoxide radical, singlet oxygen, and peroxideswhen irradiated with UVA or blue light.²⁷⁹ In addition,all-trans-retinal can stimulate increasedlevels of reactive oxygen species in a NADPH oxidase-dependent manner.^531,532 Unless quickly dissipated, such reactive oxygen species can causeoxidative damage to lipids and proteins that compromise photoreceptorstructure and function.⁵³³ Yet anotherconsequence of elevatedall-trans-retinal concentrationsis the accelerated formation and accumulation of bis-retinoid lipofuscinchromophores within retina and RPE.^{314,401,520,534,535} Although formation of the Schiff base adduct ofall-trans-retinal with PE is fully reversible, reaction ofN-ret-PE with a second molecule ofall-trans-retinalcan initiate a cascade of irreversible nonenzymatic conversions thatlead to the production of fluorescent diretinal compounds, includingpyridinium bisretinoid (A2E) (Figure34) andretinaldehyde dimer (RALdi) (Figure35). Thecommon precursor in the biosynthesis of these fluorophores is protonatedN-ret-PE, that undergoes spontaneous tautomerizationvia an H-shift [1,6] generating phosphatidyl analogs ofenamine.^536,537 The subsequent reaction witha second molecule ofall-trans-retinal can occurthrough amine condensation followed by 6π-electrocyclizationto generate a reduced form of A2E, phosphatidyl-dihydropyridine bisretinoid(A2PE-H₂) (Figure34). Alternatively,the nucleophilic carbon 20 of theN-ret-PE tautomercan react with carbon 13 ofall-trans-retinalvia [1,4] conjugate addition. Consequent Mannich condensationthen leads to the RALdi precursor (Figure35).⁵³⁴ The strong kinetic isotope effectobserved in RALdi synthesis as compared to that found for A2E supportsthis reaction mechanism^537,538 Aromatization of thedihydropyridine in A2PE-H₂ eliminates two hydrogens toyield phosphatidyl-pyridinium bisretinoid (A2PE) whereas the RALdiprecursor spontaneously rearranges to eliminate the amino group ofPE (Figures34 and35, respectively). In the final stage of A2E biosynthesis, its immediateprecursor, A2PE, is either hydrolytically cleaved by enzymatic actionof phosphodiesterase, which can occur in ROS before internalizationby the RPE, or undergoes nonenzymatic acid-catalyzed hydrolysis insideRPE phagosomes.³¹⁴ As a result of incompletelysosomal degradation, these byproducts of retinal metabolism accumulatein the RPE as residual bodies called lipofuscin. These bodies providea useful fluorescent marker for lipofuscin quantification in the livingeye, which can serve as long-lasting evidence of excessive past accumulationofall-trans-retinal.^539−541 Indeed, the primaryfluorescent components of lipofuscin areall-trans-retinal conjugates such as A2E and RALdi.⁵⁴² A2E was shown to be further metabolized by horseradish peroxidase,⁵⁴³ but there is yet no evidence that this processoccursin vivo. Lipofuscin granules contain severalchromophores absorbing UV, blue, and green light whereas A2E actsas an acceptor of energy from their photoexcited states and dissipatesthat energy mainly by thermal deactivation and partly by emittingfluorescence.⁵⁴⁴ Considering that lipofuscingranules contain potent photosensitizers, quenching of excited statesof lipofuscin photosensitizers by A2E may play a protective antioxidantrole. Yet, A2E also exhibits some minor photoreactivity and severalexperimentsin vitro demonstrated that A2E and itsoxidation products can be cytotoxic to RPE cells and trigger complementactivation and inflammatory signaling.³¹⁷ It remains to be established whether or not these deleterious propertiesof A2E are physiologically relevant.

The connection betweendelayedall-trans-retinalclearance, lipofuscin buildup, and retinal degeneration is exemplifiedby Stargardt disease, a human condition in which juvenile maculardegeneration is caused by mutations in both alleles of theABCA4 gene.^487,545 Consequently, retinal samplescollected from these patients revealed elevated levels of N-retinylidene-PEand overaccumulation of A2E in the RPE.⁵²⁹ Because the cytotoxicity of retinal conjugates has been widely accepted,it is believed that the precipitating cause of retinal degenerationin Stargardt patients is the deterioration of RPE cells responsiblefor maintenance of photoreceptors.⁵⁴⁶ However,recent studies ofAbca4^–/–Rdh8^–/– double knockout mice that closely recapitulate human retinalpathological conditions indicate thatall-trans-retinalitself may play a decisive role in light-induced photoreceptor degeneration.^318,320,531

Philip D. Kiser was bornin 1980 in Olney, IL. He received a Pharm.D.degree from the St. Louis College of Pharmacy in 2005. During pharmacyschool he performed research in the laboratories of Dr. Eric Barkerat Purdue University and Dr. Thomas Baranski at Washington University.He then entered graduate school in the Department of Pharmacologyat Case Western Reserve University (CWRU), where he earned a Ph.D.in molecular pharmacology in 2010 under the guidance of Prof. KrzysztofPalczewski. He then joined the Department of Pharmacology as an instructorin 2011, following a brief postdoctoral appointment. His primary researchinterests pertain to the biochemistry and structural biology of retinoidand carotenoid metabolism. He is also involved in teaching pharmacologyto undergraduate, graduate, and professional students at CWRU. Inhis free time, he enjoys playing and listening to music and fixingthings around the house with his three sons.

Marcin Golczakobtained his Master’s degree in Biotechnologyfrom the Wroclaw University of Technology, Poland, in 1999. He continuedresearch, working on Ca²⁺-binding proteins, at the NenckiInstitute of Experimental Biology, Polish Academy of Science in Warsaw,Poland, where he received his Ph.D. in 2003. During his subsequentpostdoctoral research in Prof. Krzysztof Palczewski’s laboratoryat the University of Washington, Seattle, WA. and Case Western ReserveUniversity, Cleveland, OH, Dr. Golczak has focused on vitamin A metabolism,especially the enzymatic pathway called the retinoid (visual) cycle,that leads to regeneration of the visual chromophore required forsight. Currently, he holds an Instructor position in the Departmentof Pharmacology at Case Western Reserve University. His main interestsare the elucidation of molecular mechanisms of vitamin A homeostasisin the eye and the development of small molecule-based therapeuticstrategies against light-induced retinal degeneration.

KrzysztofPalczewski, Ph.D., has been Chair and John H. Hord Professorof Pharmacology at Case Western Reserve University since 2005. Beforethat he was professor of Ophthalmology, Pharmacology and Chemistryat the University of Washington, Seattle. Dr. Palczewski’snotable scientific achievements span the fields of vertebrate vision,structural biology, and pharmacology, including the translation ofsome of his basic discoveries into treatments for human blinding diseases.He is author/coauthor of scientific publications involving topicssuch as the following: structures of rhodopsin, retinoid isomeraseRPE65, and other retinal proteins; transmembrane signaling; the “retinoid”or visual cycle; animal models of human blinding diseases; and retinalimaging techniques. Palczewski is recipient of several prestigiousawards, including the following: the Jules and Doris Stein Researchto Prevent Blindness Professor award; the Cogan Award from the Associationfor Research in Vision and Ophthalmology; the Knight’s Crossof the Order of Merit of the Republic of Poland award; The Roger HJohnson Macular Degeneration Award; and The Friedenwald Award. Healso is one of four recipients of the 2012 Award from Foundation forPolish Science, the highest recognition available to Polish scientistsliving outside that country. Professor Palczewski also serves on theeditorial boards of several well recognized biochemical journals andNational Institute of Health scientific panels appropriate to hisfield.

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