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Sirtuin 2

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Available structures
PDBOrtholog search: PDBe RCSB
AliasesSIRT2, SIR2, SIR2L, SIR2L2, sirtuin 2
External IDsOMIM: 604480; MGI: 1927664; HomoloGene: 40823; GeneCards: SIRT2; OMA:SIRT2 - orthologs
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 19: 38.88 – 38.9 MbChr 7: 28.47 – 28.49 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene.[5][6][7] SIRT2 is an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status.[8] Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord.[9]


Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.[7] Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system[citation needed] and gluconeogenesis.[10] There is growing evidence for additional functions of SIRT2 in the nucleus. During the G2/M transition, nuclear SIRT2 is responsible for global deacetylation of H4K16, facilitating H4K20 methylation and subsequent chromatin compaction.[11] In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo.[12] Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.[13]



Human SIRT2 gene has 18 exons resides on chromosome 19 at q13.[7] For SIRT2, four different human splice variants are deposited in the GenBank sequence database.[14]


SIRT2 gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene.[7] Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A leucine-rich nuclear export signal (NES) within the N-terminal region of these two isoforms is identified.[14] Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.[15]

Selective ligands[edit]


  • Benzamide compound # 64[16]
  • (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3[17]
  • 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM[18]
  • AGK2 (C23H13Cl2N3O2; 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide) is a potent, cell-permeable, selective SIRT2 inhibitor that minimally affects both SIRT1 and SIRT3[19]

Animal studies[edit]

Metabolic actions[edit]

SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity.[20] SIRT2 is responsible for the deacetylation and activation of G6PD, stimulating pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.[21]


Several studies in cell and invertebrate models of Parkinson's disease (PD) and Huntington's disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members.[22][23] In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.[24]

Clinical significance[edit]

Metabolic actions[edit]

Several SIRT2 deacetylation targets play important roles in metabolic homeostasis. SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect against insulin resistance. SIRT2 sensitizes cells to the action of insulin by physically interacting with and activating Akt and downstream targets. SIRT2 mediates mitochondrial biogenesis by deacetylating PGC-1α, upregulates antioxidant enzyme expression by deacetylating FOXO3a, and thereby reduces ROS levels.

Cell cycle regulation[edit]

Although preferentially cytosolic, SIRT2 transiently shuttles to the nucleus during the G2/M transition of the cell cycle, where it has a strong preference for histone H4 lysine 16 (H4K16ac),[25] thereby regulating chromosomal condensation during mitosis.[26] During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division.[15] Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.[27]


Mounting evidence implies a role for SIRT2 in tumorigenesis. SIRT2 may suppress or promote tumor growth in a context-dependent manner. SIRT2 has been proposed to act as a tumor suppressor by preventing chromosomal instability during mitosis.[28] SIRT2-specific inhibitors exhibits broad anticancer activity.[29][30]


SIRT2 has been shown to interact with:


  1. ^ a b c ENSG00000068903 GRCh38: Ensembl release 89: ENSG00000283100, ENSG00000068903Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015149Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ^ a b c d "Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)".
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  9. ^ Maxwell MM, Tomkinson EM, Nobles J, Wizeman JW, Amore AM, Quinti L, Chopra V, Hersch SM, Kazantsev AG (Oct 2011). "The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS". Human Molecular Genetics. 20 (20): 3986–96. doi:10.1093/hmg/ddr326. PMC 3203628. PMID 21791548.
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  19. ^ Wawruszak A, Luszczki J, Czerwonka A, Okon E, Stepulak A (2022-04-04). "Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells". Cells. 11 (7): 1211. doi:10.3390/cells11071211. ISSN 2073-4409. PMC 8998062. PMID 35406775. This article incorporates text from this source, which is available under the CC BY 4.0 license.
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  21. ^ a b Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, Ling ZQ, Hu FJ, Sun YP, Zhang JY, Yang C, Yang Y, Xiong Y, Guan KL, Ye D (Jun 2014). "Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress". The EMBO Journal. 33 (12): 1304–20. doi:10.1002/embj.201387224. PMC 4194121. PMID 24769394.
  22. ^ Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG (Jul 2007). "Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease". Science. 317 (5837): 516–19. Bibcode:2007Sci...317..516O. doi:10.1126/science.1143780. PMID 17588900. S2CID 84493360.
  23. ^ Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, Moffitt H, Smith DL, Runne H, Gokce O, Kuhn A, Xiang Z, Maxwell MM, Reeves SA, Bates GP, Neri C, Thompson LM, Marsh JL, Kazantsev AG (Apr 2010). "SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 107 (17): 7927–32. Bibcode:2010PNAS..107.7927L. doi:10.1073/pnas.1002924107. PMC 2867924. PMID 20378838.
  24. ^ Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, Rauf NA, Wang H, Silverman RB, Ayata C, Maxwell MM, Steegborn C, Schwarzschild MA, Outeiro TF, Kazantsev AG (2015). "The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia". PLOS ONE. 10 (1): e0116919. Bibcode:2015PLoSO..1016919C. doi:10.1371/journal.pone.0116919. PMC 4301865. PMID 25608039.
  25. ^ Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R, Reinberg D (May 2006). "SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis". Genes & Development. 20 (10): 1256–61. doi:10.1101/gad.1412706. PMC 1472900. PMID 16648462.
  26. ^ Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, Yamaguchi S, Nakano S, Katoh M, Ito H, Oshimura M (Feb 2007). "SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress". Oncogene. 26 (7): 945–57. doi:10.1038/sj.onc.1209857. PMID 16909107. S2CID 21357335.
  27. ^ Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA (May 2003). "Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle". Molecular and Cellular Biology. 23 (9): 3173–85. doi:10.1128/mcb.23.9.3173-3185.2003. PMC 153197. PMID 12697818.
  28. ^ Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, Ji J, Wang XW, Park SH, Cha YI, Gius D, Deng CX (Oct 2011). "SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity". Cancer Cell. 20 (4): 487–99. doi:10.1016/j.ccr.2011.09.004. PMC 3199577. PMID 22014574.
  29. ^ Jing H, Hu J, He B, Negrón Abril YL, Stupinski J, Weiser K, Carbonaro M, Chiang YL, Southard T, Giannakakou P, Weiss RS, Lin H (Mar 2016). "A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity". Cancer Cell. 29 (3): 297–310. doi:10.1016/j.ccell.2016.02.007. PMC 4811675. PMID 26977881.
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Further reading[edit]

External links[edit]

  • Overview of all the structural information available in the PDB for UniProt: Q8IXJ6 (NAD-dependent protein deacetylase sirtuin-2) at the PDBe-KB.