title: Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5.
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.
authors: Sirtris, a GSK Company, 200 Technology Square, Cambridge, Massachusetts 02139, USA. bruce.2.szczepankiewicz@gsk.com
authors: Bruce G
authors: BG
authors: Szczepankiewicz
authors: Han
authors: H
authors: Dai
authors: Karsten J
authors: KJ
authors: Koppetsch
authors: Dongming
authors: D
authors: Qian
authors: Fan
authors: F
authors: Jiang
authors: Cheney
authors: C
authors: Mao
authors: Robert B
authors: RB
authors: Perni
mesh_terms: D054329:Carbasugars / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009243:NAD / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D056566:Sirtuin 3 / Q000737:chemistry* / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D054329:Carbasugars; D009243:NAD; C508544:SIRT5 protein, human; D056566:Sirtuin 3; D037761:Sirtuins