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Figure 1
The NAD+-dependent deacylases share a highly conserved catalytic core that consists of a larger NAD+-binding domain and a smaller zinc-binding domain. (a) Structural sequence alignment of the deacylase domains of human Sirt1 (UniProt Q96EB6; amino acids 244–495), human Sirt2 (UniProt Q8IXJ6; amino acids 65–337) and human Sirt3 (UniProt Q9NTG7; amino acids 126–379). The Sirt2-specific insertion is marked in yellow. The deacylase domains of Sirt1, Sirt2 and Sirt3 share a sequence identity of 44%. (b) Superposition of the deacylase domains of apo Sirt1 (teal; PDB entry 4ig9), apo Sirt2 (brown; PDB entry 3zgo) and apo Sirt3 (light grey; PDB entry 3gls). The NAD+-binding domain of Sirt1, Sirt2 and Sirt3 is very similar, while the zinc-binding domain is structurally more variable. (c) Proposed mechanism of sirtuin-catalyzed deacetylation. The carbonyl O atom of the acetyl group attacks the C1′ atom of the ribose. On nicotinamide cleavage, the acetyl group is then transferred via an alkylimidate and a bicyclic intermediate to the 2′-­hydroxy group of the ribose. The deacetylated lysine is subsequently released. The final reaction product 2′-O-AADPR equilibrates non-enzymatically with 3′-O-AADPR. Deacylation is thought to take place using a similar mechanism.

ISSN: 2053-230X
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