SIRT2 (sirtuin 2; HGNC:10886, NCBI Gene ID 22933) is a human locus mapped to chromosome band 19q13.2 that encodes class III NAD+-dependent cytosolic deacetylase & long-chain deacylase Sirtuin 2 (389 aa; EC 2.3.1.286). SIRT2 acts in deacetylation of alpha-tubulin (Lys40), histone H4K16 during mitosis, G6PD (pentose phosphate NADPH) & BubR1 stabilization, together with SIRT1 (Nuclear Sirtuin 1 Paralog Gene), SIRT3 (Mitochondrial Sirtuin 3 Paralog Gene), and Tubulin (Deacetylated at Alpha-Tubulin Lys40 by SIRT2). Encodes the predominantly cytosolic NAD+-dependent deacetylase sirtuin 2 that regulates alpha-tubulin acetylation, oligodendrocyte myelination, and the mitotic checkpoint.
Approved Symbol
SIRT2
Chromosomal Locus
19q13.2
Encoded Product
Class III NAD+-dependent cytosolic deacetylase & long-chain deacylase Sirtuin 2 (389 aa; EC 2.3.1.286)
Primary Pathway
Deacetylation of alpha-tubulin (Lys40), histone H4K16 during mitosis, G6PD (pentose phosphate NADPH) & BubR1 stabilization
Clinical / Therapeutic Role
Most abundant sirtuin in adult brain & oligodendrocytes; BubR1 deacetylation extends lifespan in progeroid models
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 16-exon gene on chromosome 19q13.2 generating three alternatively spliced isoforms (389-residue isoform 1, 352-residue brain-enriched isoform 2, and isoform 5), featuring a classical Rossmann-fold NAD+-binding catalytic core with a hydrophobic pocket capable of removing both acetyl groups and long-chain myristoyl/lactoyl acyl modifications.
Cellular & Tissue Expression Profile: Unique among mammalian sirtuins in being predominantly cytoplasmic during interphase, and representing the single most abundantly expressed sirtuin in the adult central nervous system—particularly inside myelinating oligodendrocytes and Schwann cells—as well as hepatocytes and adipocytes.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: In the cytosol, SIRT2 deacetylates alpha-tubulin at Lys40 to regulate microtubule dynamics and axonal transport, deacetylates glucose-6-phosphate dehydrogenase (G6PD) to stimulate NADPH production and glutathione antioxidant regeneration, and deacetylates the mitotic checkpoint kinase BubR1 (BUB1B at Lys668) to prevent ubiquitin-mediated BubR1 degradation; upon nuclear envelope breakdown at the G2/M transition, SIRT2 enters chromatin to deacetylate histone H4 at Lys16 (H4K16ac) and facilitate chromosome condensation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Age-related decline of NAD+ and SIRT2 activity leads to loss of mitotic checkpoint protein BubR1 and aneuploidy, whereas transgenic overexpression of SIRT2 or NAD+ restoration stabilizes BubR1 and doubles median lifespan in BubR1-hypomorphic progeroid mice; in hepatocyte-specific aged models, SIRT2 also suppresses NLRP3 inflammasome activation.
Therapeutic & Clinical Pharmacology: Context-dependent therapeutic target: while elevating NAD+-SIRT2 activity protects against vascular aging, insulin resistance, and demyelination, selective brain-penetrant SIRT2 inhibitors (such as AGK2 and SirReal2) have been investigated to increase alpha-tubulin acetylation and autophagic clearance of alpha-synuclein in Parkinson disease models.