Sirtuins, a class of enzymes known as nicotinamide adenine
dinucleotide-dependent deacetylases, have been shown to regulate a variety of biological processes, including aging, transcription, and metabolism. Severn human Sirtuins members (Sirt1-7) are involved in various kinds of severe diseases like aging, cancer development, autoimmune diseases and therefore are considered as potential drug targets for treatment. Among them, Sirt4-7 have very weak traditional deacetylation function in contrast to the others. So, investigation on the real functions of these sirtuins is a prerequisite for specific modulator (inhibitor or activator) design. Crystallography is a robust way to study the molecular basis of the catalytic function of these sirtuins. Here we show that the real function of Sirt6 is the de-long-chain-fatty acylase activity from lysine, such as the demyristoylase activity. The crystal structure of Sirt6 complex shows a large hydrophobic pocket accommodating the myristoyl group. Together with the biochemical and physiological data from our collaborators, we confirm that Sirt6 promotes the TNFα secretion via hydrolysis the myristoyl group on K19 and K20. Fatty acylation on lysine occurs in mammalian cells and had been found for years, however, the regulatory mechanism is still unclear. Our results provide the opportunities to understand the regulatory of the long chain fatty acyl modification on lysine via Sirt6, which has been little studied until now. More work will be focused on the structural based development of inhibitors to cure the Sirt6 regulated diseases in the near future. / published_or_final_version / Physiology / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/196481 |
| Date | January 2013 |
| Creators | Wang, Yi, 王毅 |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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