Structure-based Mechanism of ADP-ribosylation by Sirtuins

Journal Article · Tue Dec 01 04:00:00 EST 2009 · J. Biol. Chem.

DOI:https://doi.org/10.1074/jbc.M109.024521· OSTI ID:1005988

Hawse, William F; Wolberger, Cynthia

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.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1005988
• Journal Information: J. Biol. Chem., Journal Name: J. Biol. Chem. Journal Issue: (48) ; 09, 2009 Vol. 284; ISSN JBCHA3; ISSN 0021-9258
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
AGING
ARGININE
ENZYMES
LYSINE
METABOLISM
PEPTIDES
REACTION INTERMEDIATES
REGULATIONS
RESIDUES
SUBSTRATES
TRANSCRIPTION