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postgraduate thesis: Structural basis on human Sirt6 function of hydrolyzing long chain fatty acyl lysine

TitleStructural basis on human Sirt6 function of hydrolyzing long chain fatty acyl lysine
Authors
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wang, Y. [王毅]. (2013). Structural basis on human Sirt6 function of hydrolyzing long chain fatty acyl lysine. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5177302
AbstractSirtuins, 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.
DegreeDoctor of Philosophy
SubjectSirtuins
Lysine
Dept/ProgramPhysiology
Persistent Identifierhttp://hdl.handle.net/10722/196481

 

DC FieldValueLanguage
dc.contributor.authorWang, Yi-
dc.contributor.author王毅-
dc.date.accessioned2014-04-11T23:14:29Z-
dc.date.available2014-04-11T23:14:29Z-
dc.date.issued2013-
dc.identifier.citationWang, Y. [王毅]. (2013). Structural basis on human Sirt6 function of hydrolyzing long chain fatty acyl lysine. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5177302-
dc.identifier.urihttp://hdl.handle.net/10722/196481-
dc.description.abstractSirtuins, 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.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshSirtuins-
dc.subject.lcshLysine-
dc.titleStructural basis on human Sirt6 function of hydrolyzing long chain fatty acyl lysine-
dc.typePG_Thesis-
dc.identifier.hkulb5177302-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePhysiology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5177302-

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