Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations.

ABSTRACT: Sir2 enzymes catalyze the NAD+-dependent protein deacetylation and play critical roles in epigenetics, cell death, and lifespan regulation. In spite of a current flurry of experimental studies, the catalytic mechanism for this unique and important class of enzymes remains elusive. Employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the B3LYP/6-31G(d) QM/MM potential and the umbrella sampling method, we have characterized the initial step of the Sir2Tm-catalyzed reaction, which is also the most controversial portion of its mechanism. Our results indicate that the nicotinamide cleavage reaction employs a highly dissociative and concerted displacement mechanism: the cleavage of the glycosidic bond is facilitated by the nucleophilic participation of the acetyl-lysine, and

SUBMITTER: Hu P 

PROVIDER: S-EPMC2627508 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature