title: Poly(ADP-ribose)-polymerase-catalyzed hydrolysis of NAD+: QM/MM simulation of the enzyme reaction.
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.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bellocchi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Re
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marrone
authors.forename: Cecilia
authors.initials: C
authors.lastname: Coletti
mesh_terms: D002384:Catalysis; D006868:Hydrolysis; D008958:Models, Molecular; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: D011065:Poly(ADP-ribose) Polymerases