The Retinaldehyde Reductase Activity of DHRS3 Is Reciprocally Activated by Retinol Dehydrogenase 10 to Control Retinoid Homeostasis

• Published in: The Journal of biological chemistry 2014-05, Vol.289 (21), p.14868-14880
• Main Authors: Adams, Mark K., Belyaeva, Olga V., Wu, Lizhi, Kedishvili, Natalia Y.
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Animals; Biocatalysis; Blotting, Western; Cells, Cultured; Dehydrogenase; Enzyme Activation; Female; HEK293 Cells; Hep G2 Cells; Homeostasis; Humans; In Situ Hybridization; Limb Buds - embryology; Limb Buds - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Protein Binding; Reductase; Retinaldehyde - metabolism; Retinoid; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sf9 Cells; Vitamin A; Vitamin A - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.552257

The retinoic acid-inducible dehydrogenase reductase 3 (DHRS3) is thought to function as a retinaldehyde reductase that controls the levels of all-trans-retinaldehyde, the immediate precursor for bioactive all-trans-retinoic acid. However, the weak catalytic activity of DHRS3 and the lack of changes in retinaldehyde conversion to retinol and retinoic acid in the cells overexpressing DHRS3 undermine its role as a physiologically important all-trans-retinaldehyde reductase. This study demonstrates that DHRS3 requires the presence of retinol dehydrogenase 10 (RDH10) to display its full catalytic activity. The RDH10-activated DHRS3 acts as a robust high affinity all-trans-retinaldehyde-specific reductase that effectively converts retinaldehyde back to retinol, decreasing the rate of retinoic acid biosynthesis. In turn, the retinol dehydrogenase activity of RDH10 is reciprocally activated by DHRS3. At E13.5, DHRS3-null embryos have ∼4-fold lower levels of retinol and retinyl esters, but only slightly elevated levels of retinoic acid. The membrane-associated retinaldehyde reductase and retinol dehydrogenase activities are decreased by ∼4- and ∼2-fold, respectively, in Dhrs3−/− embryos, and Dhrs3−/− mouse embryonic fibroblasts exhibit reduced metabolism of both retinaldehyde and retinol. Neither RDH10 nor DHRS3 has to be itself catalytically active to activate each other. The transcripts encoding DHRS3 and RDH10 are co-localized at least in some tissues during development. The mutually activating interaction between the two related proteins may represent a highly sensitive and conserved mechanism for precise control over the rate of retinoic acid biosynthesis. DHRS3 is thought to be important for retinoid metabolism but it is unclear whether it has significant retinaldehyde reductase activity. DHRS3 requires RDH10 for full enzymatic activity and, in turn, activates RDH10. The mutually activating relationship allows for precise control over retinoic acid biosynthesis. This is a previously unrecognized regulatory mechanism that may be conserved across species.