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

doi:10.1007/s11030-019-09971-2

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 journal › Article › peer-review

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 language	English
Journal	Molecular Diversity
DOIs	https://doi.org/10.1007/s11030-019-09971-2
Publication status	Published - Jan 1 2019

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

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10.1007/s11030-019-09971-2

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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 journal › Article › peer-review

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

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doi = "10.1007/s11030-019-09971-2",

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T1 - Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules

AU - Sociali, Giovanna

AU - Liessi, Nara

AU - Grozio, Alessia

AU - Caffa, Irene

AU - Parenti, Marco Daniele

AU - Ravera, Silvia

AU - Tasso, Bruno

AU - Benzi, Andrea

AU - Nencioni, Alessio

AU - Del Rio, Alberto

AU - Robina, Inmaculada

AU - Millo, Enrico

AU - Bruzzone, Santina

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.].

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.].

KW - Molecular design

KW - Sirtuins

KW - Small molecule SIRT6 modulators

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

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Keywords

ASJC Scopus subject areas

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