Synthesis and biochemical evaluation of non-hydrolyzable analogs of O-acetyl-ADP-ribose

AEI 10

Lindsay R. Comstock, lrcomstock@wisc.edu and John M. Denu, jmdenu@wisc.edu. Department of Biomolecular Chemistry, University of Wisconsin-Madison, 551 MSC, 1300 University Ave, Madison, WI 53706
The identification of a novel class of HDACs, the silent information regulator 2 (Sir2 or sirtuin) family of histone/protein deacetylases, has led to the characterization of a NAD+-dependent process that is coupled with the formation of O-acetyl-ADP-ribose as the primary product. Due to the inherent instability of O-acetyl-ADP-ribose, its hydrolysis has hindered efforts thus far to investigate its role in cellular pathways. In an effort to generate a biochemical tool to carry out such investigations, non-hydrolyzable analogs of O-acetyl-ADP-ribose containing an N-acetyl moiety have been generated. The ability of these N-acetyl analogs to mimic the authentic metabolite will be evaluated using known targets of O-acetyl-ADP-ribose.