title: SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator.
abstract: SIRT1 is a protein deacetylase that has emerged as a therapeutic target for the development of activators to treat diseases of aging. SIRT1-activating compounds (STACs) have been developed that produce biological effects consistent with direct SIRT1 activation. At the molecular level, the mechanism by which STACs activate SIRT1 remains elusive. In the studies reported herein, the mechanism of SIRT1 activation is examined using representative compounds chosen from a collection of STACs. These studies reveal that activation of SIRT1 by STACs is strongly dependent on structural features of the peptide substrate. Significantly, and in contrast to studies reporting that peptides must bear a fluorophore for their deacetylation to be accelerated, we find that some STACs can accelerate the SIRT1-catalyzed deacetylation of specific unlabeled peptides composed only of natural amino acids. These results, together with others of this study, are at odds with a recent claim that complex formation between STACs and fluorophore-labeled peptides plays a role in the activation of SIRT1 (Pacholec, M., Chrunyk, B., Cunningham, D., Flynn, D., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., Qiu, X., Stockman, B., Thanabal, V., Varghese, A., Ward, J., Withka, J., and Ahn, K. (2010) J. Biol. Chem. 285, 8340-8351). Rather, the data suggest that STACs interact directly with SIRT1 and activate SIRT1-catalyzed deacetylation through an allosteric mechanism.
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: Han
authors: H
authors: Dai
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: Lauren
authors: L
authors: Kustigian
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: David
authors: D
authors: Carney
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: April
authors: A
authors: Case
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: Thomas
authors: T
authors: Considine
authors: Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115.
authors: Basil P
authors: BP
authors: Hubbard
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: Robert B
authors: RB
authors: Perni
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: Thomas V
authors: TV
authors: Riera
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: Bruce
authors: B
authors: Szczepankiewicz
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139.
authors: George P
authors: GP
authors: Vlasuk
authors: From Sirtris, a GSK Company, Cambridge, Massachusetts 02139. Electronic address: rstein@sirtrispharma.com.
authors: Ross L
authors: RL
authors: Stein
mesh_terms: D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry*; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D056564:Sirtuin 1 / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D020536:Enzyme Activators; D010455:Peptides; C447939:SIRT1 protein, human; D056564:Sirtuin 1