Poly(ADP‐Ribose)‐Polymerase‐Catalyzed Hydrolysis of NAD+: QM/MM Simulation of the Enzyme Reaction
- 2 May 2006
- journal article
- research article
- Published by Wiley in ChemMedChem
- Vol. 1 (5) , 533-539
- https://doi.org/10.1002/cmdc.200500061
Abstract
Poly(ADP‐ribose) polymerase (PARP) is a nuclear enzyme which uses NAD+ as substrate and catalyzes the transfer of multiple units of ADP‐ribose to target proteins. PARP is an attractive target for the discovery of novel therapeutic agents and PARP inhibitors are currently evaluated for the treatment of a variety of pathological conditions such as brain ischemia, inflammation, and cancer. Herein, we use the PARP‐catalyzed reaction of NAD+ hydrolysis as a model for gaining insight into the molecular details of the catalytic mechanism of PARP. The reaction has been studied in both the gas‐phase and in the enzyme environment through a QM/MM approach. Our results indicate that the cleavage reaction of the nicotinamide‐ribosyl bond proceeds through an SN2 dissociative mechanism via an oxacarbenium transition structure. These results confirm the importance of the structural water molecule in the active site and may constitute the basis for the design of transition‐state‐based PARP inhibitors.Keywords
This publication has 40 references indexed in Scilit:
- QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activationChemical Communications, 2005
- Simulating enzyme reactions: Challenges and perspectivesJournal of Computational Chemistry, 2001
- Ab Initio QM/MM Study of the Citrate Synthase Mechanism. A Low-Barrier Hydrogen Bond Is not InvolvedJournal of the American Chemical Society, 2000
- Transition State Analysis of NAD+Hydrolysis by the Cholera Toxin Catalytic SubunitJournal of the American Chemical Society, 1997
- The IMOMO method: Integration of different levels of molecular orbital approximations for geometry optimization of large systems: Test for n-butane conformation and S N2 reaction: RCl+Cl−The Journal of Chemical Physics, 1996
- Hydrolysis of (2-Deoxy-.beta.-D-glucopyranosyl)pyridinium SaltsJournal of the American Chemical Society, 1995
- Role of Glutamic Acid 988 of Human Poly-ADP-ribose Polymerase in Polymer FormationJournal of Biological Chemistry, 1995
- A quantum chemical study of the type IV nucleophilic substitution reaction and dissociation of the .beta.-nicotinamide glycosyl bond in the gas phase using semiempirical PM3 calculationsJournal of the American Chemical Society, 1992
- Pyridine nucleotide chemistry. A new mechanism for the hydroxide-catalyzed hydrolysis of the nicotinamide-glycosyl bondJournal of the American Chemical Society, 1988
- Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozymeJournal of Molecular Biology, 1976