Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators.

The Journal of Biological Chemistry
Mark A Klein, John M Denu

Abstract

Sirtuin 6 (SIRT6) is a nuclear NAD+-dependent deacetylase of histone H3 that regulates genome stability and gene expression. However, nonhistone substrates and additional catalytic activities of SIRT6, including long-chain deacylation and mono-ADP-ribosylation of other proteins, have also been reported, but many of these noncanonical roles remain enigmatic. Genetic studies have revealed critical homeostatic cellular functions of SIRT6, underscoring the need to better understand which catalytic functions and molecular pathways are driving SIRT6-associated phenotypes. At the physiological level, SIRT6 activity promotes increased longevity by regulating metabolism and DNA repair. Recent work has identified natural products and synthetic small molecules capable of activating the inefficient in vitro deacetylase activity of SIRT6. Here, we discuss the cellular functions of SIRT6 with a focus on attributing its catalytic activity to its proposed biological functions. We cover the molecular architecture and catalytic mechanisms that distinguish SIRT6 from other NAD+-dependent deacylases. We propose that combining specific SIRT6 amino acid substitutions identified in enzymology studies and activity-selective compounds could help deline...Continue Reading

References

Jul 19, 1974·Nature·M G RossmannK W Olsen
Jan 15, 1997·Genes & Development·J S Smith, J D Boeke
Nov 14, 1997·The EMBO Journal·C E FritzeR Easton Esposito
Jul 1, 1997·The International Journal of Biochemistry & Cell Biology·S P Jackson
Jan 15, 1998·Cell·D A Sinclair, L Guarente
Apr 16, 1998·The Journal of Biological Chemistry·E P RogakouW M Bonner
Sep 3, 1999·Molecular Biology of the Cell·J M ShermanL Pillus
May 17, 2000·Proceedings of the National Academy of Sciences of the United States of America·J LandryR Sternglanz
Jun 7, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S SmithJ D Boeke
Jun 30, 2000·Biochemical and Biophysical Research Communications·R A Frye
Dec 6, 2000·Proceedings of the National Academy of Sciences of the United States of America·K G TannerJ M Denu
Jun 28, 2001·Nature Structural Biology·M S FinninN P Pavletich
Sep 26, 2002·The Journal of Biological Chemistry·Kevin J BittermanDavid A Sinclair
May 20, 2003·Nature·Pere PuigserverBruce M Spiegelman
Aug 27, 2003·Nature·Konrad T HowitzDavid A Sinclair
Feb 24, 1956·Science·O WARBURG
Oct 3, 2003·The Journal of Biological Chemistry·Michael D JacksonJohn M Denu
May 20, 2004·Proceedings of the National Academy of Sciences of the United States of America·Kehao ZhaoRonen Marmorstein
Jun 11, 2004·Annual Review of Biochemistry·Gil Blander, Leonard Guarente
Mar 30, 2005·The Journal of Biological Chemistry·Gregory LisztLeonard Guarente
Jan 28, 2006·Cell·Raul MostoslavskyFrederick W Alt
May 16, 2006·Bioorganic & Medicinal Chemistry Letters·David G FatkinsWeiping Zheng
Nov 7, 2006·Nature·Joseph A BaurDavid A Sinclair
Mar 16, 2007·Structure·Anja SchuetzAlexander N Plotnikov
Apr 19, 2007·Journal of the American Chemical Society·Brian C Smith, John M Denu
Nov 22, 2007·Biochemistry·Brian C Smith, John M Denu
Jan 1, 2008·The Journal of Biological Chemistry·Terri M KowieskiJohn M Denu
Aug 2, 2008·Proceedings of the National Academy of Sciences of the United States of America·Noah DephoureSteven P Gygi

❮ Previous
Next ❯

Citations

Dec 17, 2020·Medicinal Research Reviews·Gang LiuJia Zhou
Oct 31, 2020·The Journal of Biological Chemistry·Mara CarreñoAna Denicola
Jan 15, 2021·Neurochemistry International·Hitomi MatsunoKazuhiro Sohya
Jan 18, 2021·The Journal of Biological Chemistry·Mara CarreñoAna Denicola
Apr 4, 2021·Cancers·Francesco FiorentinoDante Rotili
Jun 15, 2021·Journal of Biomolecular Structure & Dynamics·Sneha JosSivaraman Padavattan
Jul 3, 2021·Journal of Medicinal Chemistry·Francesco FiorentinoDante Rotili
Aug 17, 2021·Frontiers in Oncology·Rihan HaiGang Yin
Aug 20, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Siarhei A DabravolskiAlexander N Orekhov
Aug 26, 2021·Biological Chemistry·Anna-Theresa BlaslMichael Lammers

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

© 2022 Meta ULC. All rights reserved