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 journalArticle

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.].

Original languageEnglish
JournalMolecular Diversity
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

lysine
Sirtuin 1
Modulators
Lysine
Modulation
modulation
NAD
Molecules
molecules
modulators
Acetylation
Histones
Cytokines
Enzymes
Proteins
acetylation
secretions
biological effects
enzymes
Therapeutics

Keywords

  • 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

Cite this

Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules. / Sociali, Giovanna; Liessi, Nara; Grozio, Alessia; Caffa, Irene; Parenti, Marco Daniele; Ravera, Silvia; Tasso, Bruno; Benzi, Andrea; Nencioni, Alessio; Del Rio, Alberto; Robina, Inmaculada; Millo, Enrico; Bruzzone, Santina.

In: Molecular Diversity, 01.01.2019.

Research output: Contribution to journalArticle

Sociali, G, Liessi, N, Grozio, A, Caffa, I, Parenti, MD, Ravera, S, Tasso, B, Benzi, A, Nencioni, A, Del Rio, A, Robina, I, Millo, E & Bruzzone, S 2019, 'Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules', Molecular Diversity. https://doi.org/10.1007/s11030-019-09971-2
Sociali, Giovanna ; Liessi, Nara ; Grozio, Alessia ; Caffa, Irene ; Parenti, Marco Daniele ; Ravera, Silvia ; Tasso, Bruno ; Benzi, Andrea ; Nencioni, Alessio ; Del Rio, Alberto ; Robina, Inmaculada ; Millo, Enrico ; Bruzzone, Santina. / Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules. In: Molecular Diversity. 2019.
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AU - Tasso, Bruno

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AU - Millo, Enrico

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AB - 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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