SIRT2 (Sirtuin 2) is a NAD+-dependent deacetylase that belongs to the sirtuin family of proteins, which are conserved from yeast to humans and regulate cellular metabolism, aging, and stress responses[@sirt2018][@sirtuins2020]. SIRT2 is uniquely localized primarily in the cytoplasm, where it deacetylates various substrates including tubulin, p53, and FOXO transcription factors. The enzyme has attracted considerable interest for its roles in neurodegeneration, aging, and cancer[@sirt2021].
SIRT2 (Sirtuin 2) is a NAD+-dependent deacetylase that belongs to the sirtuin family of proteins, which are conserved from yeast to humans and regulate cellular metabolism, aging, and stress responses[@sirt2018][@sirtuins2020]. SIRT2 is uniquely localized primarily in the cytoplasm, where it deacetylates various substrates including tubulin, p53, and FOXO transcription factors. The enzyme has attracted considerable interest for its roles in neurodegeneration, aging, and cancer[@sirt2021].
Sirtuins are NAD+-dependent deacetylases that have been evolutionarily conserved from yeast to humans. The seven mammalian sirtuins (SIRT1-7) are located in different cellular compartments and perform diverse functions. SIRT2 is predominantly cytoplasmic but can shuttle to the nucleus under certain conditions, where it participates in epigenetic regulation and stress response pathways.
Structure
SIRT2 contains characteristic sirtuin features:
Rossmann fold: Core catalytic domain with NAD+ binding
Large Rossmann subdomain: Substrate binding pocket
Small subdomain: Contributes to substrate specificity
N-terminal region: Regulates protein localization
Active site: Conserved catalytic residues (H187, N188, D293)
SIRT2 exists in multiple oligomeric states and can form tetramers in cells, which may regulate its activity[@sirt2019]. The enzyme requires NAD+ as a cofactor for its deacetylase activity, linking its function to cellular metabolic status. Upon deacetylation, nicotinamide and O-acetyl-ADP-ribose are produced as byproducts.
Normal Function
Tubulin Deacetylation
SIRT2's best-characterized function is deacetylating α-tubulin:
Microtubule dynamics: Regulates microtubule stability and function