Faculty Collaboration Database

Hydrolysis of O-acetyl-ADP-ribose isomers by ADP-ribosylhydrolase 3. J Biol Chem 2011 Jun 17;286(24):21110-7

Date

04/19/2011

Pubmed ID

21498885

Pubmed Central ID

PMC3122172

DOI

10.1074/jbc.M111.237636

Scopus ID

2-s2.0-79958764081 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

O-acetyl-ADP-ribose (OAADPr), produced by the Sir2-catalyzed NAD(+)-dependent histone/protein deacetylase reaction, regulates diverse biological processes. Interconversion between two OAADPr isomers with acetyl attached to the C-2″ and C-3″ hydroxyl of ADP-ribose (ADPr) is rapid. We reported earlier that ADP-ribosylhydrolase 3 (ARH3), one of three ARH proteins sharing structural similarities, hydrolyzed OAADPr to ADPr and acetate, and poly(ADPr) to ADPr monomers. ARH1 also hydrolyzed OAADPr and poly(ADPr) as well as ADP-ribose-arginine, with arginine in α-anomeric linkage to C-1″ of ADP-ribose. Because both ARH3- and ARH1-catalyzed reactions involve nucleophilic attacks at the C-1″ position, it was perplexing that the ARH3 catalytic site would cleave OAADPr at either the 2″- or 3″-position, and we postulated the existence of a third isomer, 1″-OAADPr, in equilibrium with 2″- and 3″-isomers. A third isomer, consistent with 1″-OAADPr, was identified at pH 9.0. Further, ARH3 OAADPr hydrolase activity was greater at pH 9.0 than at neutral pH where 3″-OAADPr predominated. Consistent with our hypothesis, IC(50) values for ARH3 inhibition by 2″- and 3″-N-acetyl-ADPr analogs of OAADPr were significantly higher than that for ADPr. ARH1 also hydrolyzed OAADPr more rapidly at alkaline pH, but cleavage of ADP-ribose-arginine was faster at neutral pH than pH 9.0. ARH3-catalyzed hydrolysis of OAADPr in H(2)(18)O resulted in incorporation of one (18)O into ADP-ribose by mass spectrometric analysis, consistent with cleavage at the C-1″ position. Together, these data suggest that ARH family members, ARH1 and ARH3, catalyze hydrolysis of the 1″-O linkage in their structurally diverse substrates.

Author List

Kasamatsu A, Nakao M, Smith BC, Comstock LR, Ono T, Kato J, Denu JM, Moss J

Author

Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Diphosphate Ribose
Catalysis
Catalytic Domain
Gene Expression Regulation, Enzymologic
Glycoside Hydrolases
Hydrogen-Ion Concentration
Hydrolysis
Inhibitory Concentration 50
Models, Chemical
Models, Theoretical
N-Glycosyl Hydrolases
O-Acetyl-ADP-Ribose
Poly Adenosine Diphosphate Ribose
Protein Isoforms
Sirtuin 1
Sirtuins