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Title: Structure-based Mechanism of ADP-ribosylation by Sirtuins

Abstract

Sirtuins comprise a family of enzymes found in all organisms, where they play a role in diverse processes including transcriptional silencing, aging, regulation of transcription, and metabolism. The predominant reaction catalyzed by these enzymes is NAD{sup +}-dependent lysine deacetylation, although some sirtuins exhibit a weaker ADP-ribosyltransferase activity. Although the Sir2 deacetylation mechanism is well established, much less is known about the Sir2 ADP-ribosylation reaction. We have studied the ADP-ribosylation activity of a bacterial sirtuin, Sir2Tm, and show that acetylated peptides containing arginine or lysine 2 residues C-terminal to the acetyl lysine, the +2 position, are preferentially ADP-ribosylated at the +2 residue. A structure of Sir2Tm bound to the acetylated +2 arginine peptide shows how this arginine could enter the active site and react with a deacetylation reaction intermediate to yield an ADP-ribosylated peptide. The new biochemical and structural studies presented here provide mechanistic insights into the Sir2 ADP-ribosylation reaction and will aid in identifying substrates of this reaction.

Authors:
;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1005988
Resource Type:
Journal Article
Journal Name:
J. Biol. Chem.
Additional Journal Information:
Journal Volume: 284; Journal Issue: (48) ; 09, 2009; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AGING; ARGININE; ENZYMES; LYSINE; METABOLISM; PEPTIDES; REACTION INTERMEDIATES; REGULATIONS; RESIDUES; SUBSTRATES; TRANSCRIPTION

Citation Formats

Hawse, William F, Wolberger, Cynthia, and HHMI). Structure-based Mechanism of ADP-ribosylation by Sirtuins. United States: N. p., 2009. Web. doi:10.1074/jbc.M109.024521.
Hawse, William F, Wolberger, Cynthia, & HHMI). Structure-based Mechanism of ADP-ribosylation by Sirtuins. United States. https://doi.org/10.1074/jbc.M109.024521
Hawse, William F, Wolberger, Cynthia, and HHMI). 2009. "Structure-based Mechanism of ADP-ribosylation by Sirtuins". United States. https://doi.org/10.1074/jbc.M109.024521.
@article{osti_1005988,
title = {Structure-based Mechanism of ADP-ribosylation by Sirtuins},
author = {Hawse, William F and Wolberger, Cynthia and HHMI)},
abstractNote = {Sirtuins comprise a family of enzymes found in all organisms, where they play a role in diverse processes including transcriptional silencing, aging, regulation of transcription, and metabolism. The predominant reaction catalyzed by these enzymes is NAD{sup +}-dependent lysine deacetylation, although some sirtuins exhibit a weaker ADP-ribosyltransferase activity. Although the Sir2 deacetylation mechanism is well established, much less is known about the Sir2 ADP-ribosylation reaction. We have studied the ADP-ribosylation activity of a bacterial sirtuin, Sir2Tm, and show that acetylated peptides containing arginine or lysine 2 residues C-terminal to the acetyl lysine, the +2 position, are preferentially ADP-ribosylated at the +2 residue. A structure of Sir2Tm bound to the acetylated +2 arginine peptide shows how this arginine could enter the active site and react with a deacetylation reaction intermediate to yield an ADP-ribosylated peptide. The new biochemical and structural studies presented here provide mechanistic insights into the Sir2 ADP-ribosylation reaction and will aid in identifying substrates of this reaction.},
doi = {10.1074/jbc.M109.024521},
url = {https://www.osti.gov/biblio/1005988}, journal = {J. Biol. Chem.},
issn = {0021-9258},
number = (48) ; 09, 2009,
volume = 284,
place = {United States},
year = {Tue Dec 01 00:00:00 EST 2009},
month = {Tue Dec 01 00:00:00 EST 2009}
}