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Gene Review

Rdh5  -  retinol dehydrogenase 5

Mus musculus

Synonyms: 11-cis RDH, 11-cis RoDH, 11-cis retinol dehydrogenase, 9-cis, 9-cis retinol dehydrogenase, ...
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Disease relevance of Rdh5


High impact information on Rdh5

  • We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXR alpha, beta, and gamma [6].
  • Columbinate, similarly to linoleate, has both 9-cis and 12-cis double bonds, but it also possesses a trans double bond in the 5 position that apparently prevents its conversion to prostaglandins (PG) [7].
  • P450RA metabolizes other biologically active RAs such as 9-cis RA and 13-cis RA, but fails to metabolize their precursors, retinol and retinal [8].
  • Both Stra8 mRNA and protein were induced in cells treated by all-trans and 9-cis retinoic acids [9].
  • Interestingly, we show that the precise nature of the direct repeat response element to which RAR/RXR heterodimers are bound can affect the activity of the AF-2s of the heterodimeric partners, as well as the relative efficiency with which all-trans and 9-cis retinoic acids activate the RAR partner [10].

Chemical compound and disease context of Rdh5


Biological context of Rdh5

  • The ligand-controlled retinoic acid (RA) receptors and retinoid X receptors are important for several physiological processes, including normal embryonic development, but little is known about how their ligands, all-trans and 9-cis RA, are generated [11].
  • Double knockout mice also had normal ERG responses in dark- and light-adapted conditions, but had a further delay in dark adaptation relative to either rdh11-/- or rdh5-/- mice [12].
  • The murine cRDH gene consists of at least 5 exons and spans approximately 6 kb of genomic DNA [13].
  • Backcross analysis mapped the mouse cRDH gene to the most distal region of chromosome 10 [13].
  • The most striking phenotype of rgr-/- mice after a single flash of light includes light-dependent formation of 9-cis- and 13-cis-retinoid isomers [14].

Anatomical context of Rdh5


Associations of Rdh5 with chemical compounds

  • Here we report the identification of a stereo-specific 9-cis retinol dehydrogenase, which is abundantly expressed in embryonic tissues known to be targets in the retinoid signaling pathway [11].
  • The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid [11].
  • Retinol dehydrogenase 5 (RDH5) is responsible for a majority of the 11-cis-RDH activity in the RPE, but the formation of 11-cis-retinal in rdh5-/- mice suggests another enzyme(s) is present [12].
  • This protein also catalyzes oxidation of 13-cis-retinol at a rate approximately 10% of that of the 9-cis isomer but does not catalyze all-trans-retinol oxidation [18].
  • Taken together, these results suggest that RDH11 has a measurable role in regenerating the visual pigment by complementing RDH5 as an 11-cis-RDH in RPE cells, and indicate that an additional unidentified enzyme(s) oxidizes 11-cis-retinol or that an alternative pathway contributes to the retinoid cycle [12].

Physical interactions of Rdh5

  • Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA [19].

Enzymatic interactions of Rdh5

  • We previously reported the purification and partial amino acid (aa) sequence of a rat kidney aldehyde dehydrogenase (ALDH) isozyme that catalyzed the oxidation of 9-cis and all-trans retinal to corresponding RA with high efficiency [Labrecque et al. Biochem. J. 305 (1995) 681-684] [20].
  • A short-chain alcohol dehydrogenase has been discovered that oxidizes 9-cis- and 11-cis-retinol to their corresponding aldehydes [21].

Regulatory relationships of Rdh5

  • As 9-cis RA is about 10 times more efficient than all-trans RA in repressing Myf5, whereas TTNPB, which preferentially activates RA receptors, is far less potent, our data provide evidence for an important role of ligand-bound retinoid X-receptors in the mediation of this inhibition [22].
  • Interestingly the corresponding '9-cis analogs' are not able to bind or activate RXR alpha and show greatly reduced activity on the RARs [23].
  • Upon activation FXR heterodimerises with 9-cis retinoic X receptor (RXR) and regulates a cohort of genes involved in cholesterol catabolism and bile acids biosynthesis [24].

Other interactions of Rdh5

  • The present findings, together with those of earlier studies showing only minor functional deficits in mice deficient for Rdh5, Rdh8, or Rdh11, suggest that the activity of any one isoform is not rate limiting in the visual response [25].
  • In accordance with these HPLC observations, RDH5 and ADH4 were expressed, but no transcripts coding for enzymes that oxidise retinal to retinoic acid [26].
  • All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes [27].
  • Treatment with 9-cis, but not with all-trans RA, at primary stimulation strongly enhanced Th2 development [28].
  • All-trans-, 9-cis-, and 13-cis-retinoic acid, and the synthetic retinoid Ch55, inhibited IFN-gamma synthesis effectively, whereas retinaldehyde, retinol, and retinyl acetate did not [29].

Analytical, diagnostic and therapeutic context of Rdh5

  • Tumor weight was less in mice treated with either dose of 9-cis RA than in control mice, although this difference was not significant [30].
  • Treatment with 30 mg of 9-cis RA/kg initiated after tumor formation significantly reduced the incidence of pulmonary metastasis, compared with the control group [30].
  • All-trans RA (3 or 30 microg/kg of body weight in 0.1 ml of sesame oil), 9-cis RA (3 or 30 mg/kg in 0.1 ml of sesame oil), or sesame oil (0.1 ml; control treatment) were administered intragastrically 5 d/wk for 4 weeks beginning 3 days after transplantation (n = 4 mice/group) or after formation of a palpable tumor (5 mice/group) [30].


  1. Targeted disruption of the mouse cis-retinol dehydrogenase gene: visual and nonvisual functions. Shang, E., Lai, K., Packer, A.I., Paik, J., Blaner, W.S., de Morais Vieira, M., Gouras, P., Wolgemuth, D.J. J. Lipid Res. (2002) [Pubmed]
  2. 9-cis-retinoids: biosynthesis of 9-cis-retinoic acid. Paik, J., Vogel, S., Piantedosi, R., Sykes, A., Blaner, W.S., Swisshelm, K. Biochemistry (2000) [Pubmed]
  3. Inhibitory effects of 9-cis and all-trans retinoic acid on 1,25(OH)2 vitamin D3-induced bone resorption. Kindmark, A., Melhus, H., Ljunghall, S., Ljunggren, O. Calcif. Tissue Int. (1995) [Pubmed]
  4. The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells. Hansen, N.J., Wylie, R.C., Phipps, S.M., Love, W.K., Andrews, L.G., Tollefsbol, T.O. Int. J. Oncol. (2007) [Pubmed]
  5. Efficacy of all-trans-beta-carotene, canthaxanthin, and all-trans-, 9-cis-, and 4-oxoretinoic acids in inducing differentiation of an F9 embryonal carcinoma RAR beta-lacZ reporter cell line. Nikawa, T., Schulz, W.A., van den Brink, C.E., Hanusch, M., van der Saag, P., Stahl, W., Sies, H. Arch. Biochem. Biophys. (1995) [Pubmed]
  6. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Mangelsdorf, D.J., Borgmeyer, U., Heyman, R.A., Zhou, J.Y., Ong, E.S., Oro, A.E., Kakizuka, A., Evans, R.M. Genes Dev. (1992) [Pubmed]
  7. Effect of dietary 18-carbon fatty acids on growth of transplantable mammary adenocarcinomas in mice. Abraham, S., Hillyard, L.A. J. Natl. Cancer Inst. (1983) [Pubmed]
  8. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. Fujii, H., Sato, T., Kaneko, S., Gotoh, O., Fujii-Kuriyama, Y., Osawa, K., Kato, S., Hamada, H. EMBO J. (1997) [Pubmed]
  9. Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene. Oulad-Abdelghani, M., Bouillet, P., Décimo, D., Gansmuller, A., Heyberger, S., Dollé, P., Bronner, S., Lutz, Y., Chambon, P. J. Cell Biol. (1996) [Pubmed]
  10. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. Durand, B., Saunders, M., Gaudon, C., Roy, B., Losson, R., Chambon, P. EMBO J. (1994) [Pubmed]
  11. The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid. Romert, A., Tuvendal, P., Simon, A., Dencker, L., Eriksson, U. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  12. Delayed dark adaptation in 11-cis-retinol dehydrogenase-deficient mice: a role of RDH11 in visual processes in vivo. Kim, T.S., Maeda, A., Maeda, T., Heinlein, C., Kedishvili, N., Palczewski, K., Nelson, P.S. J. Biol. Chem. (2005) [Pubmed]
  13. Biochemical properties, tissue expression, and gene structure of a short chain dehydrogenase/ reductase able to catalyze cis-retinol oxidation. Gamble, M.V., Shang, E., Zott, R.P., Mertz, J.R., Wolgemuth, D.J., Blaner, W.S. J. Lipid Res. (1999) [Pubmed]
  14. Evaluation of the role of the retinal G protein-coupled receptor (RGR) in the vertebrate retina in vivo. Maeda, T., Van Hooser, J.P., Driessen, C.A., Filipek, S., Janssen, J.J., Palczewski, K. J. Neurochem. (2003) [Pubmed]
  15. Gene structure, expression analysis, and membrane topology of RDH4. Romert, A., Tuvendal, P., Tryggvason, K., Dencker, L., Eriksson, U. Exp. Cell Res. (2000) [Pubmed]
  16. Quantitative axial profiles of retinoic acid in the embryonic mouse spinal cord: 9-cis retinoic acid only detected after all-trans-retinoic acid levels are super-elevated experimentally. Ulven, S.M., Gundersen, T.E., Sakhi, A.K., Glover, J.C., Blomhoff, R. Dev. Dyn. (2001) [Pubmed]
  17. Modulation of resistin expression by retinoic acid and vitamin A status. Felipe, F., Bonet, M.L., Ribot, J., Palou, A. Diabetes (2004) [Pubmed]
  18. Identification and characterization of a stereospecific human enzyme that catalyzes 9-cis-retinol oxidation. A possible role in 9-cis-retinoic acid formation. Mertz, J.R., Shang, E., Piantedosi, R., Wei, S., Wolgemuth, D.J., Blaner, W.S. J. Biol. Chem. (1997) [Pubmed]
  19. Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha. Tate, B.F., Allenby, G., Janocha, R., Kazmer, S., Speck, J., Sturzenbecker, L.J., Abarzúa, P., Levin, A.A., Grippo, J.F. Mol. Cell. Biol. (1994) [Pubmed]
  20. Cloning of a cDNA encoding rat aldehyde dehydrogenase with high activity for retinal oxidation. Bhat, P.V., Labrecque, J., Boutin, J.M., Lacroix, A., Yoshida, A. Gene (1995) [Pubmed]
  21. The oxidation of 9-cis-retinol: a possible synthesis pathway for 9-cis-retinoic acid. Wolf, G. Nutr. Rev. (2000) [Pubmed]
  22. 9-cis-retinoic acid regulates the expression of the muscle determination gene Myf5. Carnac, G., Albagli-Curiel, O., Levin, A., Bonnieu, A. Endocrinology (1993) [Pubmed]
  23. Characterization of synthetic retinoids with selectivity for retinoic acid or retinoid X nuclear receptors. LeMotte, P.K., Keidel, S., Apfel, C.M. Biochim. Biophys. Acta (1996) [Pubmed]
  24. Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Rizzo, G., Renga, B., Mencarelli, A., Pellicciari, R., Fiorucci, S. Curr. Drug Targets Immune Endocr. Metabol. Disord. (2005) [Pubmed]
  25. Targeted disruption of the murine retinal dehydrogenase gene rdh12 does not limit visual cycle function. Kurth, I., Thompson, D.A., Rüther, K., Feathers, K.L., Chrispell, J.D., Schroth, J., McHenry, C.L., Schweizer, M., Skosyrski, S., Gal, A., Hübner, C.A. Mol. Cell. Biol. (2007) [Pubmed]
  26. Identification of endogenous retinoids, enzymes, binding proteins, and receptors during early postimplantation development in mouse: important role of retinal dehydrogenase type 2 in synthesis of all-trans-retinoic acid. Ulven, S.M., Gundersen, T.E., Weedon, M.S., Landaas, V.O., Sakhi, A.K., Fromm, S.H., Geronimo, B.A., Moskaug, J.O., Blomhoff, R. Dev. Biol. (2000) [Pubmed]
  27. Ligand-dependent activation of transcription in vitro by retinoic acid receptor alpha/retinoid X receptor alpha heterodimers that mimics transactivation by retinoids in vivo. Dilworth, F.J., Fromental-Ramain, C., Remboutsika, E., Benecke, A., Chambon, P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  28. Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway. Stephensen, C.B., Rasooly, R., Jiang, X., Ceddia, M.A., Weaver, C.T., Chandraratna, R.A., Bucy, R.P. J. Immunol. (2002) [Pubmed]
  29. Vitamin A down-regulation of IFN-gamma synthesis in cloned mouse Th1 lymphocytes depends on the CD28 costimulatory pathway. Cantorna, M.T., Nashold, F.E., Chun, T.Y., Hayes, C.E. J. Immunol. (1996) [Pubmed]
  30. Effect of all-trans and 9-cis retinoic acid on growth and metastasis of xenotransplanted canine osteosarcoma cells in athymic mice. Hong, S.H., Kadosawa, T., Mochizuki, M., Matsunaga, S., Nishimura, R., Sasaki, N. Am. J. Vet. Res. (2000) [Pubmed]
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