NAD-dependent protein deacetylase sirtuin 2 (SIRT2) (SIRT2)

NAD-dependent protein deacetylase sirtuin 2 (SIRT2) is a member of the sirtuin family of Class III histone deacetylases that primarily localizes to the cytoplasm but can shuttle to the nucleus and mitochondria. It plays a pivotal role in regulating the cell cycle, particularly during the G2/M transition, and maintains genomic stability by deacetylating both histones and non-histone proteins such as alpha-tubulin and p53. In oncology, SIRT2 exhibits a complex, context-dependent role, acting as a tumor suppressor in some cancers by preventing chromosomal instability while promoting progression in others, such as acute myeloid leukemia, by stabilizing oncogenic factors. It is also a significant target in neurodegenerative diseases like Parkinson's and Huntington's, where its inhibition has demonstrated neuroprotective effects by reducing protein aggregation and toxicity. Beyond these roles, SIRT2 is involved in metabolic homeostasis, inflammation, and the oxidative stress response, making it a versatile therapeutic target. Pharmacological targeting of SIRT2 with selective small-molecule inhibitors like SirReal2 and AGK2 is currently being explored in preclinical research to treat cancer and neurological disorders. However, achieving high isoform selectivity remains a major challenge due to the conserved catalytic domains shared among the sirtuin family.

Other names

Sirtuin 2SIR2SIR2LSIR2L2NAD-dependent deacetylase sirtuin-2Silent information regulator 2-like protein 2

Inhibition of NAD-dependent deacetylase activity, leading to increased acetylation of substrate proteins such as alpha-tubulin, p53, and FOXO transcription factors, thereby modulating cell cycle progression, protein stability, and metabolic pathways.