Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5.
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Szczepankiewicz BG, Dai H, Koppetsch KJ, Qian D, Jiang F, Mao C, Perni RB
Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5.
J Org Chem. 2012 Sep 7;77(17):7319-29. doi: 10.1021/jo301067e. Epub 2012 Aug 17.
- PubMed ID
- 22849721 [ View in PubMed]
- Abstract
Carba-NAD is a synthetic compound identical to NAD except for one substitution, where an oxygen atom adjacent to the anomeric linkage bearing nicotinamide is replaced with a methylene group. Because it is inert in nicotinamide displacement reactions, carba-NAD is an unreactive substrate analogue for NAD-consuming enzymes. SIRT3 and SIRT5 are NAD-consuming enzymes that are potential therapeutic targets for the treatment of metabolic diseases and cancers. We report an improved carba-NAD synthesis, including a pyrophosphate coupling method that proceeds in approximately 60% yield. We also disclose the X-ray crystal structures of the ternary complexes of SIRT3 and SIRT5 bound to a peptide substrate and carba-NAD. These X-ray crystal structures provide critical snapshots of the mechanism by which human sirtuins function as protein deacylation catalysts.