The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase

Dea Slade, Mark S. Dunstan, Eva Barkauskaite, Ria Weston, Pierre Lafite, Neil Dixon, Marijan Ahel, David Leys and Ivan Ahel ()
Additional contact information
Dea Slade: Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester
Mark S. Dunstan: Manchester Interdisciplinary Biocentre
Eva Barkauskaite: Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester
Ria Weston: Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester
Pierre Lafite: ICOA – UMR CNRS 6005 Université d’Orléans, Rue de Chartres
Neil Dixon: Manchester Interdisciplinary Biocentre
Marijan Ahel: Rudjer Boskovic Institute, Bijenicka 54
David Leys: Manchester Interdisciplinary Biocentre
Ivan Ahel: Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester

Nature, 2011, vol. 477, issue 7366, 616-620

Abstract: Taking PAR apart Proteins can be reversibly modified through the addition of repeating, polymerized ADP-ribose (PAR) subunits catalysed by poly(ADP-ribose) polymerase (PARP). Removal of PAR requires a glycohydrolase (PARG), which cleaves the ribose–ribose bond between subunits. Ivan Ahel and colleagues report that bacteria and fungi have a divergent PARG, which is unrelated to other enzymes that cleave PAR. Its structure, in complex with ADP-ribose and with a PARG inhibitor, and the results of mutational analysis suggest that the mechanism used in mammals and bacteria may be conserved. PARP inhibitors are being developed as pharmaceuticals for diseases including cancer, and this work suggests that small, cell-permeable PARG inhibitors might also be possible drug candidates.

Date: 2011
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DOI: 10.1038/nature10404

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