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Retinal

Retinal, also known as retinaldehyde, is the aldehyde form of vitamin A (retinol) and serves as the essential chromophore for vertebrate vision.^[1] With the molecular formula C₂₀H₂₈O, it features a β-ionone ring connected to a polyene chain ending in an aldehyde group, enabling light absorption in the visible spectrum.^[1] In photoreceptor cells of the retina, the 11-cis-isomer of retinal covalently binds to opsin proteins via a protonated Schiff base linkage at lysine residue 296, forming visual pigments such as rhodopsin in rods and iodopsins in cones.^[2] Upon photon absorption, 11-cis-retinal undergoes rapid photoisomerization to all-trans-retinal, triggering a conformational change in the opsin that activates the G-protein transducin and initiates the phototransduction signaling cascade, ultimately leading to hyperpolarization of the photoreceptor and neural transmission of visual information.^[2] To sustain continuous vision, retinal participates in the visual cycle, a series of enzymatic reactions primarily occurring in the retinal pigment epithelium (RPE) and photoreceptors.^[2] All-trans-retinal released from activated visual pigments is reduced to all-trans-retinol, transported to the RPE, and esterified by lecithin:retinol acyltransferase (LRAT) before isomerohydrolase RPE65 converts it to 11-cis-retinol, which is then oxidized by short-chain dehydrogenase/reductase enzymes like retinol dehydrogenase 5 (RDH5) to regenerate 11-cis-retinal.^[2] This cycle ensures a steady supply of the chromophore, with binding proteins such as cellular retinaldehyde-binding protein (CRALBP) and interphotoreceptor retinoid-binding protein (IRBP) facilitating transport and preventing toxicity from free retinal, which can accumulate and cause retinal degeneration if unregulated.^[2] Disruptions in retinal metabolism, such as mutations in RPE65 or LRAT, lead to inherited retinal dystrophies like Leber congenital amaurosis, underscoring its critical role in ocular health.^[2] Beyond vision, retinal serves as a precursor to retinoic acid, which influences gene expression via retinoid X receptors (RXRs) and retinoic acid receptors (RARs), contributing to embryonic development and epithelial maintenance, though its primary biological significance lies in phototransduction.^[1]^[3]

Chemical Structure and Properties

Molecular Composition and Isomers

Retinal, also known as retinaldehyde, has the molecular formula C20H28O and is a derivative of vitamin A characterized by a monocyclic diterpenoid structure.^[1] It features a β-ionone ring—a cyclohexene ring with a conjugated double bond, a geminal dimethyl substitution at position 1, and a methyl group at position 5—connected via a single bond to a linear polyene chain. This chain consists of four conjugated carbon-carbon double bonds and terminates in an aldehyde functional group (-CHO) at carbon 15, enabling its role as a chromophore due to the extended conjugation.^[4] The carbon skeleton of retinal spans 20 atoms, with the β-ionone ring encompassing carbons 1–6, followed by the polyene side chain (carbons 7–15) where the double bonds occur at positions 7–8, 9–10, 11–12, and 13–14. The aldehyde group at C15 imparts polarity and reactivity, while the polyene chain's conjugation delocalizes electrons, facilitating light absorption and isomerization. In text representation, the structure can be described as a β-ionone ring linked to -CH=CH-C(CH3)=CH-CH=CH-C(CH3)=CH-CHO, with specific stereochemistry at the double bonds determining the isomer.^[5] Retinal primarily exists as geometric isomers differing in the configuration of the polyene chain's double bonds, with all-trans-retinal and 11-cis-retinal being the most biologically relevant. In all-trans-retinal, all four double bonds exhibit E (trans) stereochemistry, resulting in a fully extended linear conformation. In contrast, 11-cis-retinal has Z (cis) configuration at the 11–12 double bond, introducing a bend in the chain, while the other double bonds remain E. This cis configuration strains the molecule, enabling rapid photoisomerization upon light absorption, where rotation occurs specifically around the 11–12 bond to yield the all-trans form.^[1]/Photoreceptors/Chemistry_of_Vision/Cis-Trans_Isomerization_of_Retinal) The all-trans isomer is thermodynamically more stable than the 11-cis isomer by approximately 4 kcal/mol, owing to reduced steric hindrance in its extended form. Consequently, 11-cis-retinal displays higher reactivity, being more prone to both thermal and photochemical conversion to the all-trans configuration compared to other mono-cis isomers. This instability contributes to its selective accumulation in biological systems through enzymatic control.^[6]^[7]

Physical and Spectroscopic Properties

Retinal is a lipophilic molecule characterized by poor solubility in water, approximately 0.1 μM at room temperature and pH 7.3, reflecting its nonpolar polyene structure that favors partitioning into lipid environments over aqueous media. In contrast, it exhibits good solubility in organic solvents such as ethanol (>10 mg/mL), chloroform, and diethyl ether, facilitating its extraction and handling in laboratory settings. All-trans-retinal typically presents as yellow to orange crystals or a crystalline powder, with a melting point of 62–65 °C; its boiling point is estimated at 367 °C under standard pressure, though it often decomposes before reaching this temperature due to thermal instability.^[1]^[8] The UV-Vis absorption spectrum of retinal features a prominent λ_max at approximately 380 nm for the all-trans isomer in solvents like ethanol, arising from π–π* transitions in its extended conjugated system of four double bonds and the aldehyde carbonyl.^[9] This absorption shifts modestly with isomerization, such as to around 370 nm for the 11-cis form.^[10] Fluorescence spectroscopy reveals weak emission from retinal, with a broad spectrum peaking near 500 nm upon excitation at 380 nm, attributed to its low quantum yield (<0.01) but useful for detecting trace amounts and probing excited-state dynamics in non-aqueous environments. Raman spectroscopy yields distinctive vibrational signatures for structural elucidation, including a strong all-trans indicator band at 960 cm⁻¹ from C–H out-of-plane wagging and C=C stretching modes around 1550–1580 cm⁻¹, enabling differentiation of configurational isomers without isotopic labeling. The aldehyde functionality at C-15 imparts high reactivity to retinal, rendering it susceptible to aerial oxidation, which converts it to retinoic acid via enzymatic or non-enzymatic pathways, and to nucleophilic addition forming protonated Schiff bases with primary amines such as ε-amino groups of lysine residues.^[11] These reactions underpin retinal's role in condensation processes but also contribute to its instability, necessitating storage under inert atmospheres to prevent degradation.

Biosynthesis and Metabolism

Dietary Sources and Conversion

Retinal, a key form of vitamin A, is primarily obtained through dietary sources that provide either preformed vitamin A or its provitamin precursors. Preformed vitamin A, including retinal and retinol, is found in animal-derived foods such as liver, fish, eggs, dairy products, and fish oils, where concentrations are highest in organ meats like beef liver.^[12] In contrast, provitamin A carotenoids, particularly β-carotene, serve as the main plant-based sources and are abundant in orange and green vegetables like carrots, spinach, sweet potatoes, and leafy greens, as well as in fruits such as apricots and cantaloupe.^[12] These carotenoids must undergo enzymatic conversion in the body to yield retinal, making plant sources an indirect but significant contributor to vitamin A status, especially in vegetarian diets.^[13] The conversion of provitamin A carotenoids to retinal occurs mainly in the small intestine through the action of the enzyme β-carotene 15,15'-monooxygenase 1 (BCMO1), which catalyzes the oxidative central cleavage of β-carotene at its 15,15' double bond.^[14] This symmetric cleavage reaction stoichiometrically produces two molecules of all-trans-retinal from one molecule of β-carotene, with the enzyme's activity dependent on molecular oxygen and iron as cofactors.^[15] However, the efficiency of this bioconversion varies widely among individuals due to genetic, nutritional, and health factors, with a typical weight-based ratio of approximately 12:1 (μg β-carotene to 1 μg retinol equivalents), though it can range from 3.6:1 to 28:1 in humans.^[16] Retinal produced via this pathway is rapidly reduced to retinol by retinal reductases to facilitate further transport.^[17] Following cleavage, retinal-derived retinol is esterified in enterocytes and incorporated into chylomicrons for lymphatic absorption and delivery to the liver, the primary storage site for vitamin A.^[18] From the liver, retinol is mobilized into the bloodstream bound to retinol-binding protein (RBP), often complexed with transthyretin for stability, enabling distribution to peripheral tissues.^[19] This process supports an enterohepatic circulation, where a portion of retinyl esters is recycled through bile to enhance overall bioavailability and maintain steady-state levels.^[20]

Interconversions with Vitamin A Derivatives

Retinal, the aldehyde form of vitamin A, undergoes reversible oxidation from retinol, the primary circulating form, through the action of retinol dehydrogenases (RDHs), which are predominantly members of the short-chain dehydrogenase/reductase (SDR) superfamily.^[21] This bidirectional reaction is catalyzed by enzymes such as RDH10, which exhibits high catalytic efficiency with a Km value of approximately 0.035 μM for all-trans-retinol, making it a key player in maintaining retinal levels.^[22] The reverse reaction, reducing retinal back to retinol, is facilitated by retinal reductases like RDH11 and RDH12, which prefer NADP(H) as a cofactor and show Km values around 0.12 μM for retinaldehyde.^[21] These enzymes are widely distributed, with RDH10 being ubiquitously expressed, particularly during embryogenesis, while RDH11 displays broad tissue presence including liver and lung.^[22] The irreversible oxidation of retinal to retinoic acid, the transcriptionally active form of vitamin A, is mediated by retinal dehydrogenases (RALDHs), also known as ALDH1A enzymes.^[21] Key isoforms include RALDH1 (ALDH1A1), primarily expressed in adult liver; RALDH2 (ALDH1A2), crucial for embryonic development with expression in mesodermal tissues; and RALDH3 (ALDH1A3), found in adult tissues like skin and lung.^[21] Kinetic parameters vary, with RALDH2 showing a Km of 0.66 μM for retinaldehyde and high efficiency (Vmax around 200 nmol/min/mg), while RALDH3 has a Km of 3.9 μM but superior overall activity (Vmax 306 nmol/min/mg).^[21] This step commits retinal to signaling pathways, including brief roles in gene regulation via nuclear receptors.^[21] For long-term storage, retinol is esterified to retinyl esters primarily in hepatic stellate cells through the enzyme lecithin:retinol acyltransferase (LRAT), which transfers an acyl group from phosphatidylcholine to retinol.^[23] These esters accumulate in lipid droplets within stellate cells, accounting for over 70% of the body's vitamin A reserves, and are mobilized via hydrolysis when needed.^[24] LRAT expression is highest in liver, ensuring regulated storage independent of immediate metabolic demands.^[23] Regulatory enzymes in these interconversions include alcohol dehydrogenases (ADHs), such as ADH1 and ADH4, which provide auxiliary oxidation of retinol to retinal under high-vitamin A conditions, with Km values typically in the 10-100 μM range for retinol.^[21] The SDR family dominates physiological regulation, encompassing multiple RDH isoforms with tissue-specific kinetics; for instance, RoDH4 (SDR9C8) has a Km of about 1 μM for retinol and is liver-enriched.^[21] These enzymes collectively fine-tune retinal availability, preventing toxicity from excess accumulation.^[21]

Role in Animal Vision

Binding to Opsins and Pigment Formation

Opsins are a family of G-protein-coupled receptors characterized by seven transmembrane α-helices, serving as the protein moiety in visual pigments found in the photoreceptor cells of the vertebrate retina. In rod cells, the primary opsin is rhodopsin, while cone cells express three distinct types of cone opsins responsible for color discrimination. The chromophore 11-cis-retinal binds covalently to a conserved lysine residue—specifically Lys296 in bovine rhodopsin—via a protonated Schiff base linkage, forming the functional light-sensitive pigment.^[25]^[26]^[27] This binding results in the formation of visual pigments with specific absorption properties. Rhodopsin exhibits an absorption maximum at approximately 500 nm, enabling high sensitivity to dim light in rod-mediated scotopic vision. In contrast, cone opsins, historically referred to as iodopsins, display absorption maxima tuned to different spectral regions: short-wavelength-sensitive (SWS) opsins around 420 nm for blue light, middle-wavelength-sensitive (MWS) opsins around 530 nm for green, and long-wavelength-sensitive (LWS) opsins around 560 nm for red, facilitating trichromatic color vision in humans and many primates.^[28]^[29]^[30] Isomer specificity is crucial for stable pigment formation, as only the 11-cis isomer of retinal forms a tight, functional complex with opsins; the all-trans isomer, produced upon light absorption, dissociates readily and does not regenerate the pigment under physiological conditions. This selectivity ensures that the visual system maintains a reservoir of the correct chromophore isomer for prompt response to light stimuli. Vertebrate opsins act as inverse agonists when bound to 11-cis-retinal, stabilizing the inactive state until photoisomerization occurs.^[31]^[32] The absorption maxima of these pigments are fine-tuned by the protonation state of the Schiff base and interactions with the surrounding protein environment. The protonated Schiff base inherently absorbs around 440 nm, but electrostatic interactions with charged residues, such as the counterion glutamate (Glu113 in rhodopsin), and hydrophobic packing within the opsin pocket induce bathochromic shifts, extending absorption into the visible spectrum. In cone opsins, variations in amino acid residues near the chromophore—particularly in the retinal binding pocket—further modulate these shifts to achieve wavelength discrimination for color vision, with key tuning sites identified in transmembrane helices.^[33]^[26]^[34]

Visual Cycle and Phototransduction

The visual cycle in vertebrate photoreceptors begins with the absorption of a photon by 11-cis-retinal bound to opsin in rhodopsin, triggering an ultrafast isomerization to all-trans-retinal within 200 femtoseconds, which initiates a series of conformational changes leading to the primary photoproduct bathorhodopsin.^[35] This isomerization, occurring in less than 1 picosecond, stores the photon's energy and propagates through intermediates such as lumirhodopsin and metarhodopsin I, culminating in the active metarhodopsin II (also known as R*) within milliseconds.^[5] Metarhodopsin II serves as the signaling state, binding and activating the heterotrimeric G protein transducin by catalyzing the exchange of GDP for GTP on its α-subunit.^[36] The activated transducin-α-GTP complex then stimulates the effector enzyme cGMP phosphodiesterase (PDE6), which hydrolyzes cyclic guanosine monophosphate (cGMP) in the rod outer segment, rapidly decreasing its concentration from approximately 5 μM in the dark to below 1 μM upon illumination.^[37] This drop in cGMP closes cGMP-gated cation channels on the plasma membrane, reducing the inward flux of Na⁺ and Ca²⁺, which hyperpolarizes the rod photoreceptor from a dark potential of about -40 mV to -70 mV, thereby modulating neurotransmitter release to bipolar cells.^[36] The process amplifies the signal, with a single photon activating hundreds of transducin molecules and thousands of PDE6 catalytic events, ensuring high sensitivity for low-light detection.^[5] All-trans-retinal is subsequently released from opsin, marking the decay of metarhodopsin II and the termination of the phototransduction cascade through GTP hydrolysis and PDE6 inhibition.^[37] Regeneration of 11-cis-retinal occurs via the visual cycle to restore rhodopsin sensitivity. In rods, all-trans-retinal is reduced to all-trans-retinol by retinol dehydrogenases (RDH8 and RDH12) in the photoreceptor, then transported to the adjacent retinal pigment epithelium (RPE) bound to interphotoreceptor retinoid-binding protein (IRBP).^[5] In the RPE, all-trans-retinol is esterified by lecithin:retinol acyltransferase (LRAT) and isomerized to 11-cis-retinol by the enzyme RPE65, a membrane-associated isomerohydrolase that uses all-trans-retinyl esters as substrate and requires a ferrous iron cofactor for activity.^[38] The 11-cis-retinol is oxidized to 11-cis-retinal, which returns to the photoreceptor for rebinding to opsin, completing the cycle in minutes under typical conditions.^[5] While rods primarily rely on this RPE-dependent cycle, cones exhibit a faster regeneration pathway involving an intra-retinal visual cycle mediated by Müller glial cells, enabling dark adaptation approximately 10 times quicker than in rods to support rapid color vision and adaptation to varying light intensities.^[39] This cone-specific cycle utilizes enzymes like retinosome-associated proteins in the retina, bypassing the slower RPE transport, and is essential for maintaining cone function under bright, dynamic lighting.^[40]

Functions in Microorganisms

Microbial Rhodopsins and Mechanisms

Microbial rhodopsins, classified as Type I rhodopsins, are a diverse family of light-activated retinal-binding proteins found primarily in archaea, bacteria, and some eukaryotes, distinct from Type II rhodopsins in animals that function as G-protein-coupled receptors for visual signaling. Unlike Type II rhodopsins, which utilize 11-cis-retinal and undergo slower signaling cascades, Type I rhodopsins employ all-trans-retinal as the chromophore and exhibit rapid photocycles enabling direct ion transport or sensory responses without dissociation of the retinal.^[41] A prototypical example is bacteriorhodopsin (BR), discovered in the archaeon Halobacterium salinarum, where it forms a light-driven proton pump in the purple membrane.^[42] Upon absorption of green light, the all-trans-retinal in BR isomerizes to 13-cis, triggering a series of conformational changes in the seven-transmembrane helix structure that translocates a proton from the cytoplasm to the extracellular space, establishing a proton gradient used for ATP synthesis via ATP synthase.^[41] This photocycle, completing in milliseconds, includes intermediates such as the red-shifted K state and the deprotonated M state, restoring the original configuration. Halorhodopsin (HR), also from H. salinarum, exemplifies anion transport among microbial rhodopsins, functioning as a chloride pump to maintain intracellular chloride balance under high-salinity conditions.^[41] Its mechanism mirrors BR's isomerization but directs inward chloride flux, with the retinal Schiff base facilitating anion binding and release through analogous photocycle states. Channelrhodopsins, such as ChR2 from the green alga Chlamydomonas reinhardtii, represent light-gated cation channels, allowing rapid influx of Na⁺, K⁺, Ca²⁺, and H⁺ upon blue light illumination.^[43] The 13-cis isomerization opens a conduction pathway, enabling depolarization for applications like optogenetics, with channel opening kinetics in the microsecond range. Sensory rhodopsins (SRs), including SRI and SRII in H. salinarum and fungal SRs, mediate phototaxis by modulating flagellar activity rather than ion pumping.^[41] Light-induced isomerization in SRs alters interactions with transducer proteins, propagating signals to alter motility toward or away from light sources, as seen in SRII's avoidance response in archaea.^[44] In microbes, retinal is synthesized de novo from β-carotene, derived via the mevalonate pathway from isopentenyl pyrophosphate, with lycopene β-cyclase (encoded by crtY in H. salinarum) converting lycopene to β-carotene as a key step before oxidative cleavage to retinal. Some bacteria, like those in marine environments, may acquire retinal externally from environmental sources, while archaea like Halobacterium rely predominantly on internal biosynthesis triggered by apoprotein expression. The diversity of microbial rhodopsins extends to over 7,000 identified sequences across prokaryotes and eukaryotes, encompassing proton pumps like proteorhodopsin in ocean bacteria, sodium pumps in marine microbes, and anion channels, reflecting adaptations to varied light and ionic environments.

Evolutionary and Biotechnological Roles

Retinal-based proteins, known as microbial rhodopsins, trace their evolutionary origins to ancient archaea, where they first enabled light-driven proton pumping for energy generation in extreme environments.^[45] Subsequent horizontal gene transfer events disseminated these genes to bacteria and eukaryotes, fostering widespread adoption across domains of life and contributing to the diversification of phototrophic mechanisms.^[45] This genetic mobility underscores the versatility of retinal as a chromophore, allowing its integration into diverse protein scaffolds for light sensing and energy transduction.^[46] The primordial role of retinal predates the emergence of animal vision by billions of years, serving primarily in microbial phototrophy to harvest solar energy and facilitate atmospheric oxygenation on early Earth.^[47] In archaea like Halobacterium salinarum, bacteriorhodopsin utilized retinal for efficient proton translocation, a process that likely influenced the evolution of oxygenic photosynthesis by competing for light resources in aquatic niches.^[47] This ancient functionality highlights retinal's foundational impact on life's adaptation to light before its co-option into complex visual systems in metazoans. In biotechnology, retinal-binding channelrhodopsins have revolutionized optogenetics, enabling precise optical control of neural activity. Pioneering work demonstrated that expressing channelrhodopsin-2 in mammalian neurons allows millisecond-precision activation via blue light, as shown in hippocampal slices and in vivo mouse brain circuits where light pulses reliably evoked action potentials and modulated behavior.^[48] This approach has facilitated mapping of neural pathways, with applications extending to therapeutic modulation of circuits in models of neurological disorders. Bacteriorhodopsin, another retinal protein, finds industrial use in holographic storage and solar energy conversion owing to its robust photocycle, which achieves near-unity quantum efficiency in proton pumping. In holography, oriented films of bacteriorhodopsin exhibit diffraction efficiencies up to 20%, enabling reversible data recording through light-induced conformational changes.^[49] For solar devices, biohybrid photovoltaic cells incorporating bacteriorhodopsin generate photocurrents with power conversion efficiencies around 0.5-2%, leveraging the protein's stability and directional charge separation for sustainable energy harvesting.^[50] Synthetic biology efforts have engineered retinal variants and rhodopsin mutants to enhance ion selectivity, expanding their utility in cellular tools. For instance, kalium channelrhodopsins from Klebsormidium nitens exhibit over 100-fold K⁺ preference over Na⁺, enabling light-gated potassium flux for precise membrane hyperpolarization in optogenetic applications.^[51] These proteins, informed by cryo-EM structures, optimize retinal's interaction with the protein pocket to tune conductance properties without compromising photocycle kinetics.^[51]

Physiological and Clinical Aspects

Health Implications of Deficiency and Excess

Deficiency in vitamin A, which limits the production of retinal, primarily manifests as night blindness due to impaired regeneration of rhodopsin, the light-sensitive pigment in rod photoreceptor cells.^[52] Prolonged deficiency progresses to xerophthalmia, a spectrum of ocular disorders including conjunctival dryness, corneal ulceration, and potentially irreversible blindness.^[53] Additionally, it compromises immune function, elevating the risk of severe infections such as diarrhea, measles, and respiratory illnesses, particularly in children.^[54] Globally, vitamin A deficiency remains a significant public health issue, affecting more than half of countries, predominantly in developing regions where an estimated 250,000–500,000 vitamin A-deficient children become blind every year, half of whom die within 12 months of losing their sight, and it increases mortality from common infections.^[54] However, global prevalence has been decreasing, with incident cases dropping from approximately 127 million in 1990 to 23 million in 2019, though it remains a concern in regions like sub-Saharan Africa and South Asia (as of 2024 data).^[55] Serum retinol levels below 20 μg/dL serve as a key biomarker for deficiency, reflecting depleted liver stores and systemic inadequacy.^[56] Excess intake of preformed vitamin A, leading to hypervitaminosis A, causes acute symptoms such as nausea, headache, and vertigo, while chronic exposure results in liver toxicity, including fibrosis and cirrhosis.^[57] Elevated retinoic acid levels from overload also pose teratogenic risks, inducing congenital malformations in the central nervous system, heart, and limbs when consumed during pregnancy.^[58] The tolerable upper intake level for adults is 3,000 μg/day to prevent these adverse effects.^[59] Vitamin A bioavailability interacts with minerals like zinc and iron; zinc deficiency hinders retinol-binding protein synthesis, impairing retinal transport, while vitamin A deficiency disrupts iron mobilization and hemoglobin formation, exacerbating anemia.^[60]^[61] Supplementation with these minerals can enhance vitamin A status indicators in deficient populations.^[62]

Therapeutic Applications and Research

Retinal, as a key component of the visual cycle, plays a central role in therapies aimed at restoring or supporting vision in degenerative eye diseases. The Age-Related Eye Disease Study (AREDS) and its follow-up AREDS2 demonstrated that high-dose supplements containing vitamins C and E, lutein, zeaxanthin, zinc, and copper can reduce the risk of progression from intermediate to advanced age-related macular degeneration (AMD) by approximately 25% in high-risk patients.^[63] The original AREDS formulation included beta-carotene (a provitamin A precursor that converts to retinal), but AREDS2 replaced it with lutein and zeaxanthin due to lung cancer risk in smokers; these formulations, now standard for AMD management, provide antioxidant support for photoreceptor health.^[64] Derivatives of retinal, such as 13-cis-retinoic acid (isotretinoin), have established therapeutic roles beyond vision. Isotretinoin is FDA-approved for severe recalcitrant nodular acne, where it reduces sebum production, prevents follicular hyperkeratinization, and exhibits anti-inflammatory effects by modulating gene expression via retinoic acid receptors.^[65] Clinical trials show remission in up to 80% of patients after a 4-5 month course at 0.5-1 mg/kg/day, though it requires strict monitoring for teratogenicity and hyperlipidemia.^[66] In genetic vision disorders, gene therapy targets defects in the retinal visual cycle; for Leber congenital amaurosis (LCA) caused by RPE65 mutations, which impair 11-cis-retinal regeneration, subretinal delivery of adeno-associated viral (AAV) vectors encoding functional RPE65 has restored enzyme activity and improved visual acuity in phase I/II trials.^[67] Patients showed sustained pupillary light responses and mobility improvements up to 3 years post-treatment, marking the first approved retinal gene therapy (Luxturna).^[68] Retinal prosthetics offer bionic alternatives for end-stage retinal diseases like retinitis pigmentosa, where photoreceptor loss disrupts phototransduction. The Argus II Retinal Prosthesis System, an epiretinal implant, bypasses damaged photoreceptors by converting camera-captured light into electrical pulses delivered to surviving retinal ganglion cells via a 60-electrode array, enabling patients to perceive light patterns, motion, and large objects.^[69] Implanted in over 350 patients worldwide since FDA approval in 2013, it improves functional vision in daily tasks, though resolution remains low (20/1260 equivalent).^[70] Ongoing refinements focus on higher electrode counts and wireless power to enhance spatial resolution.^[71] Emerging research extends retinal's derivatives to oncology and neurodegeneration. All-trans-retinoic acid (ATRA), synthesized from retinal, induces differentiation in acute promyelocytic leukemia (APL) by targeting PML-RARα fusion proteins, achieving complete remission rates over 90% when combined with arsenic trioxide.^[72] Preclinical studies explore its role in solid tumors like neuroblastoma via similar differentiation pathways.^[73] In neurodegeneration, 2020s investigations link vitamin A/retinal homeostasis to Alzheimer's disease (AD); mouse models deficient in retinal dehydrogenase show amyloid-beta accumulation and synaptic loss, while dietary vitamin A supplementation modulates gut microbiota to reduce neuroinflammation and cognitive decline.^[74] A 2024 study in Frontiers in Nutrition reported that vitamin A-enriched diets altered intestinal transcriptomes, lowering AD biomarkers in transgenic models, suggesting preventive potential.^[75] Retinal imaging also serves as a non-invasive AD biomarker, with thinning of inner retinal layers correlating to disease progression in cohort studies.^[76]

Historical Development

Early Isolation and Identification

In the early 1900s, investigations into dietary deficiencies revealed the existence of a fat-soluble nutrient essential for growth and health. In 1913, Elmer V. McCollum and Marguerite Davis isolated this factor from butter fat and egg yolk, demonstrating through rat feeding experiments that it prevented conditions like xerophthalmia and supported normal development, marking the discovery of vitamin A. The link between this nutrient and vision emerged from prior studies on retinal pigments. As early as 1877, Wilhelm Kühne isolated visual purple—later identified as rhodopsin—from frog retinas, observing its purple color in the dark and its bleaching to a yellow intermediate upon light exposure, suggesting a photochemical role in sight; this work was revisited in the 1920s and 1930s as researchers like Alfred Kühn explored its regeneration in insects and amphibians.^[77] Advancing chemical characterization, Paul Karrer determined the structure of vitamin A (retinol) in 1931 and synthesized it the following year, confirming its polyene chain via degradation and spectroscopic methods.^[78] In 1933, George Wald extracted vitamin A from mammalian retinas and verified its identity through absorption spectroscopy, showing maxima at 325 nm matching synthetic standards, while collaborating with Karrer to analyze samples from cattle, sheep, and pigs.^[79] These efforts relied on bioassays measuring growth restoration in vitamin A-deficient rats and color reactions like the antimony trichloride test for potency, alongside rudimentary UV-visible spectroscopy to detect carotenoid-like bands. The specific isolation of retinal, the aldehyde form critical to visual pigments, occurred in the mid-1940s. In 1944, Richard A. Morton and T. W. Goodwin oxidized vitamin A₁ to yield crystalline retinene₁, characterizing its UV-vis absorption maximum at approximately 380 nm and its color reaction absorption at 664 nm in the antimony trichloride test, confirming its role as a chromophore. By 1946, S. Ball, Goodwin, and Morton established retinene₁ as the aldehyde of vitamin A₁ through reduction back to retinol and comparative spectroscopy, solidifying its structural identity without altering the polyene backbone. Later biochemical confirmations validated these findings through enzymatic assays.

Key Discoveries and Milestones

In the 1950s and 1960s, Ruth Hubbard and George Wald made pivotal advances in elucidating the visual cycle, demonstrating that retinal undergoes a series of enzymatic conversions involving oxidation and reduction to regenerate the visual pigment rhodopsin after light exposure.^[80] Their work established that all-trans-retinal, produced upon photon absorption, is reduced to all-trans-retinol and transported to the retinal pigment epithelium for re-isomerization back to 11-cis-retinal, which then binds to opsin to reform rhodopsin. Hubbard and Wald specifically identified 11-cis-retinal as the key chromophore isomer bound to opsin in the dark-adapted state, confirming its role in the cycle through spectroscopic and biochemical analyses. This understanding of the retinoid cycle earned Wald the Nobel Prize in Physiology or Medicine in 1967, shared with Ragnar Granit and Haldan Keffer Hartline, for foundational insights into visual phototransduction.^[81] The 1970s and 1980s saw the discovery of retinal's roles beyond vertebrate vision, with Walther Stoeckenius and Dieter Oesterhelt identifying bacteriorhodopsin in 1971 as a light-driven proton pump in Halobacterium halobium, marking the first microbial rhodopsin.^[82] This protein, containing all-trans-retinal as its chromophore, undergoes photoisomerization to 13-cis-retinal upon light absorption, generating a proton gradient for ATP synthesis and expanding retinal's functional repertoire to microbial energy transduction.^[83] Subsequent studies in the 1980s revealed diverse microbial rhodopsins, such as channelrhodopsins, which facilitated ion flux and highlighted evolutionary conservation of retinal-based photobiology.^[84] During the 1990s and 2000s, structural biology advanced retinal research significantly, with Krzysztof Palczewski and colleagues determining the first crystal structure of bovine rhodopsin at 2.8 Å resolution in 2000, revealing how 11-cis-retinal binds within the seven-transmembrane helix bundle of the G-protein-coupled receptor. This structure elucidated the molecular basis of retinal's Schiff base linkage to lysine and its role in stabilizing the inactive state, providing a template for understanding phototransduction signaling.^[85] In 2005, Edward Boyden, Karl Deisseroth, and colleagues pioneered optogenetics by expressing channelrhodopsin-2—a microbial retinal-binding protein—in mammalian neurons, enabling precise optical control of neural activity with millisecond precision and transforming neuroscience tools. In the 2010s and 2020s, clinical and biophysical milestones emerged, including the 2017 FDA approval of voretigene neparvovec (Luxturna), the first gene therapy for inherited retinal dystrophy caused by RPE65 mutations, which restores the enzyme essential for 11-cis-retinal production in the visual cycle and improves vision in affected patients.^[86] Concurrently, quantum dynamics studies using femtosecond spectroscopy and time-resolved crystallography have uncovered coherent vibrational and electronic effects during retinal's ultrafast photoisomerization, occurring in femtoseconds and involving conical intersections that enhance efficiency in both rhodopsin and bacteriorhodopsin.^[87] These insights, from works like Nogly et al. in 2018, reveal quantum mechanical underpinnings of retinal's photochemistry, informing models of energy transfer in biological systems.^[6]

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ChemicalBook Provide 116-31-4(Retinal)Melting Point Boiling Point ... Boiling point: 366.92°C (rough ... all-trans-Retinal,99% all trans-Retinal,VitaminA ...<|separator|>
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Because its absorption spectrum has a λmax ~ 380 nm and extends well into the visible range, all-trans retinal can mediate oxidation by visible light.
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... λmax = 508 nm, a 68 nm red-shift as compared to the PSB of retinal in ethanol (λmax = 440 nm). In contrast to the rhodopsins and our earlier engineered ...
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The Human Enzyme That Converts Dietary Provitamin A ...
β-Carotene 15–15′-oxygenase (BCO1) catalyzes the oxidative cleavage of dietary provitamin A carotenoids to retinal (vitamin A aldehyde).
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