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

http://pubs.acs.org/doi/pdfplus/10.1021/cr400107q

Chemistry of the Retinoid (Visual) Cycle

Oxidation of retinol via retinaldehyde results in the formation of the essential morphogen all-trans-retinoic acid (ATRA). Previous studies have identified critical roles in the regulation of embryonic ATRA levels for retinol, retinaldehyde, and ATRA- oxidizing enzymes; however, the contribution of retin- aldehyde reductases to ATRA metabolism is not com- pletely understood. Herein, we investigate the role of the retinaldehyde reductase Dhrs3 in embryonic reti- noid metabolism using a Dhrs3-deficient mouse. Lack of DHRS3 leads to a 40% increase in the levels of ATRA and a 60% and 55% decrease in the levels of retinol and retinyl esters, respectively, in Dhrs3 / embryos compared to wild-type littermates. Further- more, accumulation of excess ATRA is accompanied by a compensatory 30 -50% reduction in the expression of ATRA synthetic genes and a 120% increase in the expression of the ATRA catabolic enzyme Cyp26a1 in Dhrs3 / embryos vs. controls. Excess ATRA also leads to alterations (40 - 80%) in the expression of several developmentally important ATRA target genes. Conse- quently, Dhrs3 / embryos die late in gestation and display defects in cardiac outflow tract formation, atrial and ventricular septation, skeletal develop- ment, and palatogenesis. These data demonstrate that the reduction of retinaldehyde by DHRS3 is critical for preventing formation of excess ATRA during embryonic development.—Billings, S. E., Pier- zchalski, K., Butler Tjaden, N. E., Pang, X.-Y., Trainor, P. A., Kane, M. A., Moise, A. R. The retinaldehyde reductase DHRS3 is essential for preventing the forma- tion of excess retinoic acid during embryonic develop- ment. FASEB J. 27, 000 - 000 (2013). www.fasebj.org

The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.

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Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation.

Amaryllidaceae alkaloids are an example of the vast diversity of secondary metabolites with great therapeutic promise. The identification of novel compounds in this group with over 300 known structures continues to be an area of active study. The recent identification of norbelladine 4'-O-methyltransferase (N4OMT), an Amaryllidaceae alkaloid biosynthetic enzyme, and the assembly of transcriptomes for Narcissus sp. aff. pseudonarcissus and Lycoris aurea highlight the potential for discovery of Amaryllidaceae alkaloid biosynthetic genes with new technologies. Recent technical advances of interest include those in enzymology, next generation sequencing, genetic modification, nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS).

/pdf/the-amaryllidaceae-alkaloids-biosynthesis-and-methods-for-4f33bsb56g.pdf

The Amaryllidaceae alkaloids: biosynthesis and methods for enzyme discovery

Carotenoids contribute significantly to animal body coloration, including the spectacular color pattern diversity among fishes. Fish, as other animals, derive carotenoids from their diet. Following uptake, transport and metabolic conversion, carotenoids allocated to body coloration are deposited in the chromatophore cells of the integument. The genes involved in these processes are largely unknown. Using RNA-Sequencing, we tested for differential gene expression between carotenoid-colored and white skin regions of a cichlid fish, Tropheus duboisi “Maswa”, to identify genes associated with carotenoid-based integumentary coloration. To control for positional gene expression differences that were independent of the presence/absence of carotenoid coloration, we conducted the same analyses in a closely related population, in which both body regions are white. A larger number of genes (n = 50) showed higher expression in the yellow compared to the white skin tissue than vice versa (n = 9). Of particular interest was the elevated expression level of bco2a in the white skin samples, as the enzyme encoded by this gene catalyzes the cleavage of carotenoids into colorless derivatives. The set of genes with higher expression levels in the yellow region included genes involved in xanthophore formation (e.g., pax7 and sox10), intracellular pigment mobilization (e.g., tubb, vim, kif5b), as well as uptake (e.g., scarb1) and storage (e.g., plin6) of carotenoids, and metabolic conversion of lipids and retinoids (e.g., dgat2, pnpla2, akr1b1, dhrs). Triglyceride concentrations were similar in the yellow and white skin regions. Extracts of integumentary carotenoids contained zeaxanthin, lutein and beta-cryptoxanthin as well as unidentified carotenoid structures. Our results suggest a role of carotenoid cleavage by Bco2 in fish integumentary coloration, analogous to previous findings in birds. The elevated expression of genes in carotenoid-rich skin regions with functions in retinol and lipid metabolism supports hypotheses concerning analogies and shared mechanisms between these metabolic pathways. Overlaps in the sets of differentially expressed genes (including dgat2, bscl2, faxdc2 and retsatl) between the present study and previous, comparable studies in other fish species provide useful hints to potential carotenoid color candidate genes.

/pdf/comparative-transcriptomics-reveals-candidate-carotenoid-4ncx4htmzp.pdf

Joan Giménez

Papers

Aldo-keto reductases in retinoid metabolism: Search for substrate specificity and inhibitor selectivity