4fvt | pdb_00004fvt
Human SIRT3 bound to Ac-ACS peptide and Carba-NAD
Structural highlights
Function[SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.[1] [2] [3] [4] Publication Abstract from PubMedCarba-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. Synthesis of Carba-NAD and the Structures of Its Ternary Complexes with SIRT3 and SIRT5.,Szczepankiewicz BG, Dai H, Koppetsch KJ, Qian D, Jiang F, Mao C, Perni RB J Org Chem. 2012 Jul 31. PMID:22849721[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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