Design,synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes |
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| Authors: | Angelica R Harper Anh T Le Timothy Mather Anthony Burgett William Berry Jody A Summers |
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| Institution: | 1. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States;2. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States;3. Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States |
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| Abstract: | The retinaldehyde dehydrogenase (RALDH) enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications. |
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| Keywords: | RALDH retinaldehyde dehydrogenase ATRA RAL retinaldehyde DAR ALDH aldehyde dehydrogenase |
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