Post-translational control of the long and winding road to cholesterol |
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Authors: | Laura J. Sharpe Hudson W. Coates Andrew J. Brown |
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Affiliation: | School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia |
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Abstract: | The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease. |
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Keywords: | cholesterol post-translational regulation HMGCR SM cholesterol synthesis ubiquitination phosphorylation acetylation proteasome post-translational modification cholesterol metabolism cholesterol regulation protein degradation post-translational modification (PTM) E3 ubiquitin ligase ubiquitylation (ubiquitination) ubiquitin ligase |
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