Retinal dehydrogenases

Figure 15.11 The biochemical reactions that result in the conversion of trans-retinal to ds-retinal, to continue the detection of light To continue the process, trans-retinal must be converted back to c/s-retinal. This is achieved in three reactions a dehydrogenase converts trans-retinal to trans-retinol an isomerase converts the trans-retinol to c/s-retinol and another dehydrogenase converts c/s-retinol to c/s-retinal. To ensure the process proceeds in a clockwise direction (i.e. the process does not reverse) the two dehydrogenases are separated. The trans-retinal dehydrogenase is present in the photoreceptor cell where it catalyses the conversion of trans-retinal to trans-retinol which is released into the interstitial space, from where it is taken up by an epithelial cell. Here it is isomerised to c/s-retinol and the same dehydrogenase catalyses its conversion back to c/s-retinal. This is released by the epithelial cell into the interstitial space from where it is taken up by the photoreceptor cell. This c/s-retinal then associates with the protein opsin to produce the light-sensitive rhodopsin to initiate another cycle. The division of labour between the two cells may be necessary to provide different NADH/NAD concentration ratios in the two cells. A high ratio is necessary in the photoreceptor cell to favour reduction of retinal and a low ration in the epithelial cell for the oxidation reaction (Appendix 9.7).

Retinoic acid is a metabolic product of vitamin A that supports the growth and differentiation of epithelial tissues. Retinoic acid is formed in the cytosol by the reversible oxidation of retinol to retinal, and the irreversible oxidation of retinal to retinoic acid. There is controversy as to whether retinal is oxidized by retinal dehydrogenase, which is linked to NAD+, or by retinal oxidase. 

Li, Z., V. Korzh, and Z. Y. Gong. 2007. Localized Rbp4 Expression in the YoUc Syncytial Layer Plays a Role in YoUc Cell Extension and Early Liver Development. Bmc Dev Biol 7 117. Lin, M., M. Zhang, M. Abraham, S. M. Smith, and J. L. Napoli. 2003. Mouse Retinal Dehydrogenase 4 (Raldh4), Molecular Cloning, Cellular Expression, and Activity in 9-c/r-Retinoic Acid Biosynthesis in Intact Cells. J Biol Chem 278, no 11 9856-61. 

Vitamin A (retinol) is a fat-soluble vitamin important for the maintenance of skin, bone, and blood vessels, as well as for the promotion of vision (Theodosiou et al. 2010). It is obtained from the diet either as all-trans-retinol, retinyl esters, or P-carotene (Blomhoff and Blomhoff 2006) and is stored in the liver (Moise et al. 2007). Vitamin A is converted to retinoic acid (RA), which is formed mainly through intracellular oxidative metabolism by retinal dehydrogenases (RALDHs) (Lampen et al. 2000). RA plays important roles in embryonic development, organogenesis, tissue homeostasis, cell proliferation, differentiation, and apoptosis (Theodosiou et al. 2010). In adult mammals, RALDH is found in intestinal epithelial cells (lECs) and gut associated-dendritic cells (DCs) from Peyer s patches and mesenteric lymph nodes (Iwata 2004, Coombes et al. 2007). Gut-associated DCs and lECs can metabolize vitamin A to RA in vitro (Lampen 2000), which indicates they may be a source of RA in gut mucosa. RA binds to two families of nuclear receptors, RA receptor (RAR) isotypes (a, p, and y) and retinoic X receptor (RXR) isotypes (a, p, and y). RAR and RXR form heterodimers and interact with retinoic acid response elements (RAREs) within the promoters of retinoic acid responsive genes (Blomhoff and Blomhoff 2006). RAR is ubiquitously expressed and up-regulated by RA. RXR also... 

El Akawi, Z. and Napoli, J. L (1994) Rat liver cytosolic retinal dehydrogenase, comparison of 13-cw-, 9-cis-, and all-trans-retinal as substrates and effects of cellular retinoid-binding proteins and retinoic acid on activity. Biochemistry 33, 1938-1943... 

Holo-CRBP also supports RA biosynthesis by serving as substrate for production of the intermediate retinal. Just as in RE biosynthesis with LRAT, retinal biosynthesis catalyzed by RDH does not require diffusion of retinol from holo-CRBR RDH isozymes access retinol bound in the holo-CRBP complex [5, 13-15]. Retinal dehydrogenase (RALDH) isozymes complete RA biosynthesis by irreversibly converting retinal into RA, in a step that may also involve CRBP. At least two RALDH isozymes (types 1 and 2) recognize retinal in the presence of CRBP [16-18]. 

Penzes P, Wang X, Napoli JL (1997) Enzymatic characteristics of retinal dehydrogenase type I expressed in Escherichia c(AL Biochim Biophys Acta 1342 175-181... 

Lamb AL, Wang X, Napoli JL, Newcomer ME (1998) Purification, crystallization and preliminary X-ray diffraction studies of retinal dehydrogenase type II. Acta Crystallogr 54 639-642 ... 

Lamb A, Newcomer M (1999) The structure of retinal dehydrogenase type II at 2.7 A resolution implications for retinal specificity. Biochemistry 38 m press... 

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