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

Giovanna Sociali, Nara Liessi, Alessia Grozio, Irene Caffa, Marco Daniele Parenti, Silvia Ravera, Bruno Tasso, Andrea Benzi, Alessio Nencioni, Alberto Del Rio, Inmaculada Robina, Enrico Millo, Santina Bruzzone

Research output: Contribution to journalArticlepeer-review


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.].

Original languageEnglish
JournalMolecular Diversity
Publication statusPublished - Jan 1 2019


  • Molecular design
  • Sirtuins
  • Small molecule SIRT6 modulators

ASJC Scopus subject areas

  • Catalysis
  • Information Systems
  • Molecular Biology
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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