Chemistry of the Retinoid (Visual) Cycle

As succinctly summarized by Wolf,1 lack of vitamin A (all-trans-retinol) was recognized by ancient Egyptians as causing a visual deficiency involving the retina and cornea that could be cured by eating liver. One of the symptoms of vitamin A deficiency is night blindness or nyctalopia (from Greek νύκτ-, nykt – night; and αλαός, alaos – blindness), recognized by ancient Greeks, including Hippocrates, as affecting the retina.2 In 1913 McCollum showed that “fat-soluble factor A” was essential for growth of a rat colony (reviewed in ref (3)). The treatment of factor A-deficiency included liver or liver extracts, but later in 1930 Moore found that yellow pigment (carotene) was a good substitute for this therapy.4 A major breakthrough occurred in 1931 when the chemical structures for β,β-carotene and retinol (its all-trans isomer now known as vitamin A) were determined by Karrer and colleagues.5 But, it was Wald who discovered that retinol derivatives constitute the chemical basis of our vision,6 a contribution subsequently recognized by a Nobel Prize award in 1967. In 1950–1960, a variety of vitamin A metabolic transformations, including oxidation/reduction and esterification, were elucidated by Olson,7−20 Goodman,21−32 Chytil and Ong,33−41 and Norum and Blomhoff.42−57 The discovery that one set of these metabolites, namely retinoic acids, plays a key role in the nuclear regulation of a large number of genes added a notable dimension to our knowledge of gene expression. This mechanism is also a critical player in the successful healing of corneal wounds,58 a second manifestation of vitamin A-deficiency recognized earlier. Further progress in understanding the multiple physiological roles of retinoids has been made in recent years, due mainly to the successful application of modern scientific technology. Examples include enzymology combined with structural biology, in vivo imaging based on retinoid fluorescence, improvements in analytical methods, generation and testing of animal models of human diseases with specific pathogenic genetics, genetic analysis of human conditions related to changes in vitamin A metabolism, and pharmacological approaches to combat these diseases. In this review we focus on the involvement of retinoids in supporting vision via light-sensitive rod and cone photoreceptor cells in the retina. We begin with a brief description of isopentenyl diphosphate (IPP) biosynthesis, which is essential for carotenoid (C40 isoprenoid) production. Certain of these colored compounds, such as lutein, are deposited in our retina’s macula, appearing as a “yellow” spot. Other carotenoids containing at least one unmodified β-ionone ring (represented by β,β-carotene and cryptoxanthin) serve as precursors of all-trans-retinal. Many different compounds can be generated from this monocyclic diterpenoid, which contains a β-ionone ring and polyene chain with a C15 aldehyde group. Among the numerous enzymatic activities that contribute to retinoid metabolism, polyene trans/cis isomerization is a particularly fascinating reaction that occurs in specialized structures of the retina based on a two cell system comprised of retinal photoreceptor cells and the retinal pigment epithelium (RPE). A specific enzyme system, called the retinoid (visual) cycle, has evolved to accomplish retinoid isomerization that is required for visual function in vertebrates. Individual enzymes of this pathway harbor secrets about the molecular mechanisms of this chemical transformation. Malfunctions of these processes or other pathological reactions often precipitate severe retinal pathologies. This review attempts to balance contributions that have been published over the past decades and does not intend to replace the views of investigators with different perspectives of retinoid chemistry in the eye.59−85