Characterization of human short chain dehydrogenase/reductase SDR16C family members related to retinol dehydrogenase 10. (1st October 2017)

• Record Type: Journal Article
• Authors: Adams, Mark K.; Lee, Seung-Ah; Belyaeva, Olga V.; Wu, Lizhi; Kedishvili, Natalia Y.
• Is Part Of: Chemico-biological interactions. Volume 276(2017)
• Page Start: 88
• Page End: 94
• Publication Date: 2017-10-01
• Subjects: Retinol -- Dehydrogenase -- Epidermal -- Human; SDR short-chain dehydrogenase/reductase -- RDH Retinol Dehydrogenase -- RALDH retinaldehyde dehydrogenase -- RA all-trans-retinoic acid -- RAR retinoic acid receptors -- HEK 293 cells human embryonic kidney 293 cells -- CRBP1 cellular retinol binding protein 1; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.10.019
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: All- trans -retinoic acid (RA) is a bioactive derivative of vitamin A that serves as an activating ligand for nuclear transcription factors, retinoic acid receptors. RA biosynthesis is initiated by the enzymes that oxidize retinol to retinaldehyde. It is well established that retinol dehydrogenase 10 (RDH10, SDR16C4), which belongs to the 16C family of the short chain dehydrogenase/reductase (SDR) superfamily of proteins, is the major enzyme responsible for the oxidation of retinol to retinaldehyde for RA biosynthesis during embryogenesis. However, several lines of evidence point towards the existence of additional retinol dehydrogenases that contribute to RA biosynthesis in vivo . In close proximity to RDH10 gene on human chromosome 8 are located two genes that are phylogenetically related to RDH10 . The predicted protein products of these genes, retinol dehydrogenase epidermal 2 (RDHE2, SDR16C5) and retinol dehydrogenase epidermal 2-similar (RDHE2S, SDR16C6), share 59% and 56% sequence similarity with RDH10, respectively. Previously, we showed that the single ortholog of the human RDHE2 and RDHE2S in frogs, Xenopus laevis rdhe2, oxidizes retinol to retinaldehyde and is essential for frog embryonic development. In this study, we explored the potential of each of the two human proteins to contribute to RA biosynthesis. The results of this study demonstrate that human RDHE2 exhibits a relatively low but reproducible activity when expressed in either HepG2 or HEK293 cells. Expression of the native RDHE2 is downregulated in the presence of elevated levels of RA. On the other hand, the protein encoded by the human RDHE2S gene is unstable when expressed in HEK293 cells. RDHE2S protein produced in Sf9 cells is stable but has no detectable catalytic activity towards retinol. We conclude that the human RDHE2S does not contribute to RA biosynthesis, whereas the low-activity RA-sensitive human RDHE2 may have a role in adjusting the cellular levels of RA in accord with specific physiological conditions. Highlights: The role of proteins RDHE2 and RDHE2S in retinoic acid synthesis was characterized. RDHE2 encoded by SDR16C5 gene functions as a low activity retinol dehydrogenase. Expression of endogenous RDHE2 is downregulated by treatment with retinoic acid. RDHE2S encoded by SDR16C6 gene is unstable and inactive towards retinol. In humans, RDHE2S is a pseudogene, but RDHE2 is a functional retinol dehydrogenase.