Isoprenoids: 2. Retinoids (Vitamin A)
That a dietary factor was involved in visual acuity was known to the ancient Egyptians and Greeks, but it was the 1930s before the importance of the carotenoids and their metabolites was recognized, and β-carotene and retinol were fully characterized. It is now recognized that vitamin A activity now resides in the metabolites retinol, retinal and retinoic acid, and in several provitamin A carotenoids, most notably β-carotene. A share in the Nobel Prize for Medicine in 1967 was awarded to George Wald, who over many years showed how retinol derivatives (named for their function in the retina) constituted the chemical basis of vision. Now, it is recognized that retinol, retinoic acid and their many metabolites have innumerable other functions in human metabolism from embryogenesis to adulthood, including growth and development, reproduction, cancer and resistance to infection. They are important natural antioxidants with benefits to health, although some potentially harmful properties have been reported.
Carotenoids are a class of highly unsaturated terpenoids that occur in innumerable molecular forms (>1000). They are common colourful pigments of plants, fungi, and bacteria, of vital importance to photosynthesis, and as dietary constituents they can add ornament to some animal species. Apart from acting as precursors of retinoids, carotenoids per se appear to have a relatively limited range of functions in animal tissues, but they are important to vision and as antioxidants, especially in skin. They do of course have important functions in plants and lower organisms where they originate, but this topic can only be dealt with briefly here. Other fat-soluble vitamins tocopherols (vitamin E), vitamin K and vitamin D are discussed in separate web pages.
1. Occurrence and Basic Metabolism of Carotenoids and Retinoids
The term ‘vitamin A’ is used to denote retinol (or all-trans-retinol) together with a family of biologically active C20 retinoids derived from this ('vitamers'). These are only found in animal tissues, where they are essential to innumerable biochemical processes. However, they cannot be synthesised de novo in animals and their biosynthetic precursors are plant carotenoids (provitamin A), C40 tetraterpenes of which β-carotene is most the efficient; it is an orange-red pigment that occurs in the photosynthetic tissues of plants and in seed oils. In the human diet in the developed world, plant sources tend to be less important than those from dairy products, meat, fish oils and margarines, which provide vitamin A per se, although carrots and spinach are good sources of the provitamin. In the U.K., for example, all vegetable spreads must be supplemented with the same level of vitamin A (synthetic retinol or β-carotene) as is found in butter. While most research effort has been focused on retinoids, there is increasing interest on the biological activities of intact carotenoids in animal tissues.
The biosynthesis of carotenoids in plants via isopentenyl diphosphate and dimethylallyl diphosphate has much in common with that of the plant sterols, but this is too specialized a topic to be treated at length here (but see the reading list at the end of this page). They have many important functions in plants, for example during photosynthesis or as precursors of plant hormones, and these are discussed below. Some crop plants with increased carotene levels are available with the aim of preventing vitamin A deficiency in the populations of developing countries, and further efforts are underway. Non-photosynthetic bacteria produce a different range of carotenoids, some with chain lengths other than C40 (C30 to C50).
In animals (including humans), dietary carotenoids such as β-carotene are solubilized with other dietary lipids in mixed micelles with the aid of bile acids, and they are absorbed in the intestines in intact form by a process facilitated by specific receptor proteins. Dietary retinol and retinol esters are absorbed similarly in the intestines, but the latter are first hydrolysed by pancreatic lipase. Conversion to retinoids leading ultimately to retinol esters occurs in the enterocytes, where dietary β-carotene is subjected to oxidative cleavage at its centre, the first step of which is catalysed by a cytosolic enzyme β-carotene-15,15'-oxygenase-1 (BCO1), which is specific for carotenes with a β-ionone ring, to yield two molecules of all-trans-retinal, which is reversibly reduced by a retinol reductase to retinol. Xanthophyll carotenoids are absorbed without cleavage mainly.
Any unchanged β-carotene and newly formed retinol esters in the enterocytes are incorporated into chylomicrons and released into the lymphatic system and thence into the bloodstream, where some is taken up by peripheral tissues, before most is absorbed by the liver. Some intact carotene and other carotenoids are transferred to lipoproteins (LDL and HDL) for transport in plasma, with assistance from specific binding and transport proteins, and for example, carotene can be absorbed at the placental barrier and transferred to the fetus for conversion to retinoids that are essential for development. Within the hepatocytes, retinol esters are hydrolysed in the late endosomes with release of free retinol into the cytosol, from which it can be released back into the circulation, converted to retinoids or transferred to hepatic stellate cells for storage in lipid droplets, the main body reservoir of vitamin A. In these specialized cells, retinol is esterified to form retinyl palmitate by transfer of fatty acids from position sn-1 of phosphatidylcholine, mainly via the action of a membrane-bound lecithin:retinol acyltransferase (LRAT) in the endoplasmic reticulum. There are also lesser acyl-CoA dependent pathways, including an acyl CoA:retinol acyltransferase and even the enzyme diacylglycerol acyltransferase 1 (DGAT1); esterification is facilitated by binding to cellular retinol-binding protein type II (CRBP2).
Both retinol and retinoic acid are precursors of a number of metabolites (retinoids), which are required for specific purposes in tissues, by enzymatic modification of the functional groups and geometrical isomerization of the polyene chains. In the liver, activation of the retinol pathway involves first mobilization of the ester, followed by hydrolysis by retinol ester hydrolases, which includes carboxylesterase ES-10. Then, reversible oxidation of retinol to retinal is effected by one of several enzymes that include dehydrogenases and various cytochrome P450s, before some retinal is oxidized irreversibly to retinoic acid by enzymes with retinal dehydrogenase activity. On demand, conversion of retinol to retinoic acid occurs by the same mechanisms in other tissues, although for vision, retinol esters serve directly as the substrate for the formation of the visual chromophore 11‑cis-retinal (see below). Retinyl-β-D-glucoside, retinyl-β-D-glucuronide, and retinoyl-β-D-glucuronide are naturally occurring and biologically active metabolites of vitamin A, which are found in fish and mammals. Indeed, the last has similar activity to all-trans-retinoic acid without any of the unwanted side effects in some circumstances.
Cleavage of β-carotene at double bonds other than that in the centre or of a wider range of other carotenoids occurs by the action of a related enzyme β-carotene-9',10'-dioxygenase (β-carotene-oxygenase‑2 or BCO2) in mitochondria, which leads to the formation of similar molecules, i.e. β-apocarotenals and β-apocarotenones of variable chain-length. While these may exert distinctive biological activities in their own right, there is evidence that they can also be metabolized to form retinal.
In the aqueous environment within cells, as well as in plasma, retinol, retinal and retinoic acid are bound to retinoid-binding proteins (RBP), which solubilize, protect and in effect detoxify them. These proteins also have a role in facilitating retinoid transport and metabolism; some are present only in certain tissues, and many are specific for particular retinoids and metabolic pathways. To prevent infiltration through the kidneys, retinol and holo-RBP form an association in blood with a protein termed transthyretin (TTR), which also serves as a thyroid hormone carrier and is essential for secretion. Normally, vitamin A circulates in plasma as a retinol:RBP:TTR complex with a 1:1:1 molar ratio. Unesterified retinol is the main form of the vitamin that is exported from the liver upon demand, and it is transported in blood in this bound form in VLDL, LDL and HDL (see our web page on lipoproteins), with some directly from the diet in the chylomicrons and their remnants. Peripheral tissues have specific receptors to take up what they require, probably after hydrolysis of any esters to retinol by means of the enzyme lipoprotein lipase. Then, retinol dissociates from the protein as it forms a complex with a receptor (STRA6) at a target cell and diffuses through the plasma membrane, a process driven by retinol esterification.
The RBP-TTR complex does not bind to retinal and retinoic acid, although these do bind to RBP on its own, and most of the low levels of retinoic acid transported in blood are bound to albumin. Local levels of retinoic acid are the result of an interplay between enzymes of synthesis, binding and catabolism. For example, within cells retinoic acid binding proteins (CRABP1 and CRABP2) bind to the newly synthesised retinoic acid, increase its rate of metabolism and protect cells from an excess.
Geranylgeranoic acid has structural similarities to retinoic acid and has been termed an acyclic retinoid, although it has no vitamin A activity. It is synthesised in animal tissues from mevalonate, and together with its 2,3-dihydro metabolite, has potent anticancer properties.
Retinol esters: A relatively small proportion of the cellular retinoids is located in membranes in tissues. Rather, retinol esters, mainly retinyl palmitate, are the main storage form of vitamin A, and they occur in many different organs, including adipose tissue and testes, but chiefly in stellate cells of the liver and pancreas. How the retinol is directed specifically to these cells and enters them prior to esterification is not known. Although hepatic stellate cells are much smaller and less abundant than hepatocytes (only 5 to 8% of all liver cells), they are characterized by cytoplasmic lipid droplets that contain 90-95% of the hepatic retinoids (and up to 80% of the body pool) in addition to other non-retinoid lipids; the lecithin:retinol acyltransferase is the only retinol ester synthase in this instance. In addition, specialized cells in the eye store retinoids essential for vision in the form of lipid droplets. When the supply of retinol in the diet is limited, hepatic stores of retinol esters are mobilized as retinol ester hydrolases are activated to maintain constant circulating retinol levels; hormone-sensitive lipase is the most important of these enzymes, although the adipose tissue triacylglycerol lipase and the lysosomal acid lipase are also involved.
Catabolism: All-trans-retinoic acid formation is irreversible, so its synthesis and degradation must be tightly regulated. As a first step in catabolism, the excess is cleared by conversion to more polar metabolites through oxidation by various enzymes of the cytochrome P450 family. Secondly, the water-soluble retinoic acid metabolites, including 4-hydroxy-, 4-oxo- and 18-hydroxy-retinoic acids, conjugate with glucuronic acid and then can be rapidly removed from circulation and eliminated from the body via the kidney.
2. Retinoids and Vision
It has long been know that retinoids are essential for vision, and there is now a good appreciation of how this works at the molecular level. In the eye, uptake of retinol from the circulation is mediated by the transmembrane cell-surface STRA6 receptor of the retinal pigment epithelium, a pigmented monolayer of cells located between the photoreceptors and choroid that nourishes retinal visual cells and catalyses the release of retinol from retinol-binding proteins and transports it to the cytosol. The process by which light is converted to a signal recognized by the brain, sometimes termed the 'retinoid (visual) cycle', requires a two-cell system beginning in the retinal pigment epithelium and continuing in photoreceptor cells, i.e. retinal rod and cone cells in the eye that contain membranous vesicles that serve as light receptors. Roughly half of the proteins in these vesicles consist of the protein conjugate, rhodopsin, which consists of a protein – opsin – with the retinoid 11-cis-retinal. Each step in the visual process requires specific binding or transport proteins, and especially the interphotoreceptor retinoid-binding protein (IRBP).
All-trans-retinol is first converted to its ester by the enzyme lecithin:retinol acyltransferase as described above in the RPE, and the products coalesce into lipid droplets, i.e. dynamic organelles termed 'retinosomes'. The next step involves a dual purpose enzyme (RPE65) in the endoplasmic reticulum, which cleaves the O-alkyl bond (not a conventional hydrolysis reaction) in the retinol ester and at the same time effects a change in the geometry of the double bond in position 11 of retinol from trans to cis. The 11-cis-retinol is then oxidized to 11-cis-retinal by 11-cis-retinal dehydrogenase (RDH5).
The final part of the cycle occurs in the photoreceptor, where first the 11-cis-retinal is reacted with opsin to produce the protein conjugate rhodopsin in a protonated form. When rhodopsin is activated by light, the cis-double bond in the retinoid component is isomerized non-enzymatically by the energy of a photon to the 11‑trans form with a change of conformation that in turn affects the permeability of the membrane and influences calcium transport. This results in further molecular changes that culminate in the release of opsin and all-trans-retinal, which is the trigger that sets off the nerve impulse so that the light is perceived by the brain.
A second mechanism for 11-cis-retinal formation that may function to ensure continuous visual responsiveness in bright light involves the (RPE)-retinal G protein-coupled receptor (RGR), which can function as a retinaldehyde photoisomerase. As the enzyme RPE65 functions optimally under low light conditions, it is believed that RGR prevents the saturation of photoreceptors under high light levels, and in this way facilitates vision in daylight. The isomerase, RPE65, and the photoisomerase, RGR, operate together to provide a sustained supply of the visual chromophore under different levels of illumination.
The all-trans-retinal is removed from the photoreceptor either by reduction to all-trans-retinol by all-trans-retinol dehydrogenase 8 expressed in the outer segments of photoreceptors or after transport by means of a specific transporter (ABCA4), which provides phosphatidylethanolamine (PE) for conversion to the Schiff-base adduct, i.e. N-retinylidene-phosphatidylethanolamine, which it flips from the lumen to the cytosolic leaflet of the disc membrane. This process prevents non-specific aldehyde activity with the effect of removing potentially toxic retinoid compounds from the photoreceptors. The adduct is a transient sink that dissociates so the retinal can be reduced back to all-trans-retinol by the cytoplasmic retinol dehydrogenase. All-trans-retinol exits the photoreceptor and enters the retinal pigment epithelium with the aid of binding to the retinoid-binding protein (IRBP) where it is converted back to a retinyl ester to complete the cycle and restore light sensitivity.
As a side-reaction, some troublesome bis-retinoid adducts of PE may be produced that accumulate with age and can affect vision (see our web page on phosphatidylethanolamine).
Lower organisms: Bacteriorhodopsin is the best studied of a family of opsins, found in archaea, eubacteria, fungi, and algae. It is a protein with seven transmembrane domains that acts as an opto-electrical transducer or light-gated active ion pump to captures photon energy via its covalently bound chromophore, all-trans-retinal, converting it to 13-cis-retinal, and moves protons against their electrochemical gradient from the cytoplasm to the extracellular space. In Archaea, it is known as the "purple membrane" and can occupy a high proportion of the surface area of the organism.
3. Other Functions of Retinoids in Health and Disease
In addition to their function in vision, it is now realized that retinoids have essential roles in growth and development, reproduction and resistance to infection. They are particularly important for the function of epithelial cells in the digestive tract, lungs, nervous system, immune system, skin and bone at all stages of life. They are required for the regeneration of damaged tissues, including the heart, and they appear to have some potential as chemo-preventive agents for cancer and for the treatment of skin diseases such as acne. Under pathological conditions, stellate cells lose their retinoid content and transform into fibroblast-like cells, contributing to the fibrogenic response. Cirrhosis of the liver is accompanied by a massive loss of retinoids, but it is not clear whether this is a cause or a symptom, and there appears to be confusion as to when supplementation may be helpful in this and other diseases of the liver. Like retinol and retinoic acid, the metabolite 9-cis-retinoic acid also has valuable pharmaceutical properties.
With such a large number of double bonds in conjugation, it is not surprising that carotenoids in general and retinoids in particular are efficient quenchers of singlet oxygen and scavengers of other reactive oxygen species. These antioxidant properties are believed to be important in terms of general health, but it is not clear how relevant the physical properties of retinoids are to specific biochemical processes in comparison to their effects on signalling and gene transcription. In fact, nutritional studies with dietary supplements of carotenoids have sometimes suggested pro-oxidant activity. One explanation for detrimental effects may be that regeneration of the parent carotenoid or retinoid from the corresponding radical cation may be limited when concentrations of reductants such as ascorbic acid are low.
Many of the retinol metabolites function as ligands to activate specific transcription factors for particular receptors in the nucleus of the cell, and thus they control the expression of a large number of genes (>500), including those essential to the maintenance of normal cell proliferation and differentiation, embryogenesis, for a healthy immune system, and for male and female reproduction. In the innate immune system, vitamin A is required for the differentiation of cells such as macrophages, neutrophils and natural killer cells, while all-trans-retinoic acid is involved in differentiating the precursors of dendritic cells. Retinoic acid and its 9-cis-isomer are especially important in this context, and they are often considered the most important retinoids in terms of function other than in the eye.
In essence, retinoic acid moves to the nucleus with the aid of small intracellular lipid-binding proteins (CRABP2 and FABP5), which channel it to specific nuclear receptors, the retinoic acid receptors (RAR) of which there are three, RAR-α, β and γ. These are ligand-dependent regulators of transcription and they function in vivo as heterodimers with retinoid X receptors (RXR) to process the retinoic acid signal. Similarly, 9-cis-retinoic acid and 9-cis-13,14-dihydroretinoic acid are high-affinity ligands for RXR in mice. Together with retinoic acid, these are also ligands for the farnesoid X receptor (FXR), which forms a heterodimer with RXR. The latter receptor complex is involved primarily in bile acid homeostasis, and conversely, there are suggestions that bile acids may have regulatory effects upon vitamin A homeostasis.
In addition, other nuclear receptors, such as the peroxisome proliferator-activated receptor PPARγ forms a heterodimer with the retinoid X receptor and is activated by retinoic acid to recruit cofactors. This complex in turn binds to the peroxisome proliferator response element (PPRE) gene promoter, leading to regulation mainly of those genes involved in lipid and glucose metabolism, including some involved in inflammation and cancer. To add to the complexity, retinoic acid has extra-nuclear, non-transcriptional effects, such as the activation of protein kinases and other signalling pathways.
It has also become evident that many of the functions of retinoids are mediated via the action of specific binding proteins (as discussed briefly above), which control their metabolism in vivo by reducing the effective or free retinoid concentrations, by protecting them from unwanted chemical attack, and by presenting them to enzyme systems in an appropriate conformation. With some tissues, retinol-bound RBP in blood is recognized by the membrane protein STRA6, which transports retinol into cells where it binds to an intracellular retinol acceptor, cellular retinol-binding protein 1 (CRBP1), and is then able to activate a signalling cascade that targets specific genes. In addition, a specific retinol-binding protein secreted by adipose tissue (RPB4) is involved in the development of insulin resistance and type 2 diabetes, possibly by affecting glucose utilization by muscle tissue, with obvious application to controlling obesity. In the eye, the activity of retinoic acid during development is controlled by binding to apolipoprotein A1.
All-trans-retinoic acid has been shown to be effective against many different types of human cancers, especially in model systems but also in some clinical trials, because of its specific effects on cell proliferation, differentiation, and apoptosis (where its relatively low toxicity at normal tissue levels is a virtue). For example, it induces complete remission in most of cases of acute promyelocytic leukaemia when administered in combination with other chemotherapy techniques. Similarly, 13-cis-retinoic acid has been used successfully in the treatment of children with high-risk neuroblastoma to reduce the risk of recurrence and increase long-term survival rates. However, the efficacy of similar treatments against other types of acute myeloid leukaemia and solid tumours appears to be poor. It is hoped that current efforts to obtain a better understanding of the mechanism of the anticancer activities will lead to improved treatments. Synthetic analogues of retinoic acid, termed rexinoids, which activate retinoic X receptors, also hold promise as anti-cancer agents.
Vitamin A deficiency in children and adult patients is usually accompanied by impairment of the immune system, leading to a greater susceptibility to infection and an increased mortality rate, often with growth retardation and congenital malformations. However, vitamin A deficiency in malnourished children is the major reason for childhood mortality in the underdeveloped world, causing over 650,000 early childhood deaths annually and pediatric blindness. This is doubly tragic in that it is so easily prevented. In adults, vitamin A deprivation affects the reproductive system, inhibiting spermatogenesis in males and ovulation in females. Unfortunately, it is not always easy to distinguish between the effects of vitamin A deficiency and primary defects of retinoid signalling.
4. Functions of Xanthophylls and Other Carotenoids in Humans
Xanthophylls are plant C40 tetraterpenes that differ from the carotenoids in having oxygen atoms in the ring structures (hydroxyl, oxo or epoxyl). Lutein, zeaxanthin and meso-zeaxanthin from dietary sources, such as green leafy vegetables and yellow and orange fruits and vegetables, are found specifically in the macula of the eye in humans and other primates, i.e. the functional center of the retina in a small central pit known as the macula lutea, where they enhance visual acuity and protect the eye from high-intensity, short-wavelength visible light. They are powerful antioxidants in a region vulnerable to light-induced oxidative stress. Binding proteins specific for lutein- and zeaxanthin mediate the highly selective uptake of these carotenoids into the retina, but meso-zeaxanthin is mainly a metabolite of dietary lutein. Macular xanthophylls decrease the risk of age-related macular degeneration. In the brain, they may stimulate and maintain cognitive function in the elderly, and assist with brain development in infants. Hydroxylated xanthophylls such as lutein occur both in the free form and esterified to fatty acids; the latter are hydrolysed in the intestines when consumed by animals.
Many other carotenoids are absorbed from the diet, and are subject to oxidative cleavage or other catabolic processes, partly in the intestines and partly in other tissues after transport in the lipoproteins. Some carotenoids remain intact and are believed to act as antioxidants, and some may have specific anti-inflammatory actions. For example, carotenoids accumulate in the skin of mammals, where they may have an antioxidant and photo-protective role as well as effects on the moisture content, texture and elasticity. Lycopene may have protective effects against atherogenesis, coronary heart disease and prostate cancer.
5. Functions of Carotenoids in Plants
As carotenoids have a polyene chain of 9 to 11 double bonds in conjugation, they are able to absorb light in the gap of chlorophyll absorption, and so function as additional light-harvesting pigments in plants. Their distinctive arrangement of electronic levels gives them the capacity to transfer excitation energy from the carotenoid excited state to chlorophyll in the light-harvesting complex (photosystem II). Energy can also be transferred back from chlorophyll to carotenoids as a photoprotection mechanism. During photosynthesis, damaging species are produced by both light and oxygen with reactive oxygen species (ROS) of special concern. The energy is transferred from chlorophyll to the polyene tail of the carotenoid where electrons are moved between the carotenoid bonds until the most balanced or lowest energy state (state) is reached. While there is therefore appreciable potential for carotenoids to act as antioxidants in plants, it is uncertain how important this is from a practical functional standpoint. The length of the polyene tail of carotenoids determines which wavelengths of light will be absorbed by the plant, and those not absorbed are reflected and so determine colouration.
Carotenoids are precursors for two plant hormones and a diverse set of apocarotenoids. For example, abscisic acid is a C15 isoprenoid plant hormone, which is synthesised in plastids from the C40 carotenoid zeaxanthin. A series of enzyme-catalysed epoxidations and isomerizations is involved followed by cleavage of the intermediate product by a dioxygenation reaction and further oxidations to yield eventually abscisic acid. Functioning via signalling cascades, abscisic acid regulates innumerable biological effects in plants, especially in relation to developmental processes that including plant growth, seed and bud dormancy, embryo maturation and germination, cell division and elongation, floral growth and the control of stomatal closure. It is critical for the responses to environmental stresses, that include drought, cold and heat stress, salinity and tolerance of heavy metal ions. Similarly, strigolactones are C15 oxidation products of carotenoids that are involved in the regulation of symbiosis between plants and arbuscular mycorrhizal fungi and in interactions with plant parasites.
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