Abstract: Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD+-dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity. As expected based on the biological effects of SIRT6 deacetylase activity, compound 1 increased histone 3 lysine 9 acetylation and the activity of glycolytic enzymes. Moreover, the fact that compound 1 enhanced SIRT6 deacylase activity was accompanied by an increased TNF-α release. In conclusion, new SIRT6 modulators with a lysine-like structure were identified, with differential effects on specific SIRT6 activities. Graphic abstract: The novel SIRT6 modulator concomitantly inhibits deacetylase and enhances deacylase activity.[Figure not available: see fulltext.].

Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules

Sociali G.;Liessi N.;Grozio A.;Caffa I.;Parenti M. D.;Ravera S.;Tasso B.;Benzi A.;Nencioni A.;Millo E.;Bruzzone S.
2020-01-01

Abstract

Abstract: Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD+-dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity. As expected based on the biological effects of SIRT6 deacetylase activity, compound 1 increased histone 3 lysine 9 acetylation and the activity of glycolytic enzymes. Moreover, the fact that compound 1 enhanced SIRT6 deacylase activity was accompanied by an increased TNF-α release. In conclusion, new SIRT6 modulators with a lysine-like structure were identified, with differential effects on specific SIRT6 activities. Graphic abstract: The novel SIRT6 modulator concomitantly inhibits deacetylase and enhances deacylase activity.[Figure not available: see fulltext.].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/957901
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