Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance
Abstract Mammalian SIRT6 is a well-studied histone deacetylase that was recently shown to exhibit high protein deacylation activity enabling the removal of long chain fatty acyl groups from proteins. SIRT6 was shown to play key roles in cellular homeostasis by regulating a variety of cellular proces...
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Nature Portfolio
2018
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oai:doaj.org-article:6ccf7a040ef74caca19da73a1a727ed22021-12-02T15:07:46ZDirected evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance10.1038/s41598-018-21887-92045-2322https://doaj.org/article/6ccf7a040ef74caca19da73a1a727ed22018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21887-9https://doaj.org/toc/2045-2322Abstract Mammalian SIRT6 is a well-studied histone deacetylase that was recently shown to exhibit high protein deacylation activity enabling the removal of long chain fatty acyl groups from proteins. SIRT6 was shown to play key roles in cellular homeostasis by regulating a variety of cellular processes including DNA repair and glucose metabolism. However, the link between SIRT6 enzymatic activities and its cellular functions is not clear. Here, we utilized a directed enzyme evolution approach to generate SIRT6 mutants with improved deacylation activity. We found that while two mutants show increased deacylation activity at high substrate concentration and improved glucose metabolism they exhibit no improvement and even abolished deacetylation activity on H3K9Ac and H3K56Ac in cells. Our results demonstrate the separation of function between SIRT6 catalytic activities and suggest that SIRT6 deacylation activity in cells is important for glucose metabolism and can be mediated by still unknown acylated cellular proteins.Or GertmanDotan OmerAdi HendlerDaniel SteinLior OnnYana KhukhinMiguel PortilloRaz ZarivachHaim Y. CohenDebra ToiberAmir AharoniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) |
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Medicine R Science Q Or Gertman Dotan Omer Adi Hendler Daniel Stein Lior Onn Yana Khukhin Miguel Portillo Raz Zarivach Haim Y. Cohen Debra Toiber Amir Aharoni Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance |
| description |
Abstract Mammalian SIRT6 is a well-studied histone deacetylase that was recently shown to exhibit high protein deacylation activity enabling the removal of long chain fatty acyl groups from proteins. SIRT6 was shown to play key roles in cellular homeostasis by regulating a variety of cellular processes including DNA repair and glucose metabolism. However, the link between SIRT6 enzymatic activities and its cellular functions is not clear. Here, we utilized a directed enzyme evolution approach to generate SIRT6 mutants with improved deacylation activity. We found that while two mutants show increased deacylation activity at high substrate concentration and improved glucose metabolism they exhibit no improvement and even abolished deacetylation activity on H3K9Ac and H3K56Ac in cells. Our results demonstrate the separation of function between SIRT6 catalytic activities and suggest that SIRT6 deacylation activity in cells is important for glucose metabolism and can be mediated by still unknown acylated cellular proteins. |
| format |
article |
| author |
Or Gertman Dotan Omer Adi Hendler Daniel Stein Lior Onn Yana Khukhin Miguel Portillo Raz Zarivach Haim Y. Cohen Debra Toiber Amir Aharoni |
| author_facet |
Or Gertman Dotan Omer Adi Hendler Daniel Stein Lior Onn Yana Khukhin Miguel Portillo Raz Zarivach Haim Y. Cohen Debra Toiber Amir Aharoni |
| author_sort |
Or Gertman |
| title |
Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance |
| title_short |
Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance |
| title_full |
Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance |
| title_fullStr |
Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance |
| title_full_unstemmed |
Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance |
| title_sort |
directed evolution of sirt6 for improved deacylation and glucose homeostasis maintenance |
| publisher |
Nature Portfolio |
| publishDate |
2018 |
| url |
https://doaj.org/article/6ccf7a040ef74caca19da73a1a727ed2 |
| work_keys_str_mv |
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1718388392529494016 |