Inhibition of hepatic cholesterol biosynthesis by 3,5-dihydroxy-3,4,4-trimethylvaleric acid and its site of action |
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| Authors: | F H Hulcher |
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| Affiliation: | 1. Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan;2. Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan;3. Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Wakayama, Japan;4. Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Ishikawa, Japan;5. Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan;6. Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan;7. Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan;8. Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka 541-8567, Osaka, Japan;9. Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa 920-8641, Ishikawa, Japan;10. Division of Medical Oncology, Cancer Research Institute of Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan;11. Tumor Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK;12. Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan;1. Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, M13 9PT, UK;1. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA;2. Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA;3. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA;4. McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA;1. Department of Land Resources Management, China University of Geosciences (CUG), Hubei, Wuhan 430074, China;2. Institute of Geographic Sciences and Natural Resources Research(CAS), Beijing 100101, China;3. Department of Geography, Center for Environmental Sciences and Engineering, University of Connecticut, 215 Glenbrook Rd, Unit 4148, Storrs, CT 06269, USA |
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| Abstract: | ![]()
A new analog of mevalonic acid, 3,5-dihydroxy-3,4,4-trimethylvaleric acid, was synthesized from 4-bromoacetoxy-3,3-dimethyl-2-butanone by an internal Reformatsky reaction. The compound strongly inhibits cholesterol biosynthesis by rat liver homogenates. The inhibitor in 4 × 10−4m (dl-form) concentration decreased incorporation of mevalonate-2-14C into cholesterol by half. In the presence of this inhibitor, 5-phosphomevalonate accumulates from mevalonic acid and allylpyrophosphates could not be detected. Accumulation of the monophosphate suggests that a major site of inhibition is at the second phosphorylation step, in which 5-phosphomevalonate is converted to 5-pyrophosphomevalonate by 5-phosphomevalonic kinase. A reaction mixture was developed for optimal accumulation of 5-phosphomevalonate. The new inhibitor provides a competitive substrate that will be useful for examining the mechanism of mevalonic kinase and phosphomevalonic kinase. |
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