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Sirtuin 2

From Wikipedia, the free encyclopedia

SIRT2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSIRT2, SIR2, SIR2L, SIR2L2, sirtuin 2
External IDsOMIM: 604480; MGI: 1927664; HomoloGene: 40823; GeneCards: SIRT2; OMA:SIRT2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

22933

64383

Ensembl

ENSG00000283100
ENSG00000068903

ENSMUSG00000015149

UniProt

Q8IXJ6

Q8VDQ8

RefSeq (mRNA)

NM_001193286
NM_012237
NM_030593

NM_001122765
NM_001122766
NM_022432

RefSeq (protein)

NP_001180215
NP_036369
NP_085096

NP_001116237
NP_001116238
NP_071877

Location (UCSC)Chr 19: 38.88 – 38.9 MbChr 7: 28.47 – 28.49 Mb
PubMed search[3][4]
Wikidata
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]

Function

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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]

Structure

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Gene

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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]

Protein

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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

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Inhibitors

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  • (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3[16]
  • 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM[17]
  • 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[18]

Animal studies

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Metabolic actions

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SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity.[19] 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.[20]

Neurodegeneration

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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.[21][22] In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.[23]

Clinical significance

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Metabolic actions

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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. Also, Sirt2 can reactivate the inactive G6PD by removing the acetyaltion at K403 [24] .

Cell cycle regulation

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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]

Tumorigenesis

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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]

Interactions

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SIRT2 has been shown to interact with:

References

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  1. ^ a b c ENSG00000068903 GRCh38: Ensembl release 89: ENSG00000283100, ENSG00000068903 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015149 – Ensembl, 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.
  5. ^ Afshar G, Murnane JP (June 1999). "Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2". Gene. 234 (1): 161–168. doi:10.1016/S0378-1119(99)00162-6. PMID 10393250.
  6. ^ Frye RA (June 1999). "Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity". Biochemical and Biophysical Research Communications. 260 (1): 273–279. doi:10.1006/bbrc.1999.0897. PMID 10381378.
  7. ^ a b c d "Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)".
  8. ^ Sayd S, Junier MP, Chneiweiss H (May 2014). "[SIRT2, a multi-talented deacetylase]". Médecine/Sciences. 30 (5): 532–536. doi:10.1051/medsci/20143005016. PMID 24939540.
  9. ^ Maxwell MM, Tomkinson EM, Nobles J, Wizeman JW, Amore AM, Quinti L, et al. (October 2011). "The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS". Human Molecular Genetics. 20 (20): 3986–3996. doi:10.1093/hmg/ddr326. PMC 3203628. PMID 21791548.
  10. ^ North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (February 2003). "The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase". Molecular Cell. 11 (2): 437–444. doi:10.1016/s1097-2765(03)00038-8. PMID 12620231.
  11. ^ Serrano L, Martínez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, et al. (March 2013). "The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation". Genes & Development. 27 (6): 639–653. doi:10.1101/gad.211342.112. PMC 3613611. PMID 23468428.
  12. ^ Vempati RK, Jayani RS, Notani D, Sengupta A, Galande S, Haldar D (September 2010). "p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals". The Journal of Biological Chemistry. 285 (37): 28553–28564. doi:10.1074/jbc.M110.149393. PMC 2937881. PMID 20587414.
  13. ^ Black JC, Mosley A, Kitada T, Washburn M, Carey M (November 2008). "The SIRT2 deacetylase regulates autoacetylation of p300". Molecular Cell. 32 (3): 449–455. doi:10.1016/j.molcel.2008.09.018. PMC 2645867. PMID 18995842.
  14. ^ a b Rack JG, VanLinden MR, Lutter T, Aasland R, Ziegler M (April 2014). "Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform". Journal of Molecular Biology. 426 (8): 1677–1691. doi:10.1016/j.jmb.2013.10.027. hdl:1956/10670. PMID 24177535.
  15. ^ a b North BJ, Verdin E (August 2007). "Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis". PLOS ONE. 2 (8): e784. Bibcode:2007PLoSO...2..784N. doi:10.1371/journal.pone.0000784. PMC 1949146. PMID 17726514.
  16. ^ Fridén-Saxin M, Seifert T, Landergren MR, Suuronen T, Lahtela-Kakkonen M, Jarho EM, et al. (August 2012). "Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors". Journal of Medicinal Chemistry. 55 (16): 7104–7113. doi:10.1021/jm3005288. PMC 3426190. PMID 22746324.
  17. ^ Suzuki T, Khan MN, Sawada H, Imai E, Itoh Y, Yamatsuta K, et al. (June 2012). "Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors". Journal of Medicinal Chemistry. 55 (12): 5760–5773. doi:10.1021/jm3002108. PMID 22642300.
  18. ^ Wawruszak A, Luszczki J, Czerwonka A, Okon E, Stepulak A (April 2022). "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. PMC 8998062. PMID 35406775. This article incorporates text from this source, which is available under the CC BY 4.0 license.
  19. ^ Gomes P, Fleming Outeiro T, Cavadas C (November 2015). "Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism". Trends in Pharmacological Sciences. 36 (11): 756–768. doi:10.1016/j.tips.2015.08.001. PMID 26538315.
  20. ^ a b Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, et al. (June 2014). "Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress". The EMBO Journal. 33 (12): 1304–1320. doi:10.1002/embj.201387224. PMC 4194121. PMID 24769394.
  21. ^ Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, et al. (July 2007). "Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease". Science. 317 (5837): 516–519. Bibcode:2007Sci...317..516O. doi:10.1126/science.1143780. PMID 17588900. S2CID 84493360.
  22. ^ Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, et al. (April 2010). "SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 107 (17): 7927–7932. Bibcode:2010PNAS..107.7927L. doi:10.1073/pnas.1002924107. PMC 2867924. PMID 20378838.
  23. ^ Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, et al. (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.
  24. ^ a b Wu F, Muskat NH, Dvilansky I, Koren O, Shahar A, Gazit R, et al. (October 2023). "Acetylation-dependent coupling between G6PD activity and apoptotic signaling". Nature Communications. 14 (1): 6208. doi:10.1038/s41467-023-41895-2. PMC 10556143. PMID 37798264.
  25. ^ Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, et al. (May 2006). "SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis". Genes & Development. 20 (10): 1256–1261. doi:10.1101/gad.1412706. PMC 1472900. PMID 16648462.
  26. ^ Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, Yamaguchi S, et al. (February 2007). "SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress". Oncogene. 26 (7): 945–957. 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): 3173–3185. 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, et al. (October 2011). "SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity". Cancer Cell. 20 (4): 487–499. 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, et al. (March 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.
  30. ^ a b Xu SN, Wang TS, Li X, Wang YP (September 2016). "SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation". Scientific Reports. 6: 32734. Bibcode:2016NatSR...632734X. doi:10.1038/srep32734. PMC 5009355. PMID 27586085.
  31. ^ Yuan Q, Zhan L, Zhou QY, Zhang LL, Chen XM, Hu XM, et al. (October 2015). "SIRT2 regulates microtubule stabilization in diabetic cardiomyopathy". European Journal of Pharmacology. 764: 554–561. doi:10.1016/j.ejphar.2015.07.045. PMID 26209361.
  32. ^ Belman JP, Bian RR, Habtemichael EN, Li DT, Jurczak MJ, Alcázar-Román A, et al. (February 2015). "Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment". The Journal of Biological Chemistry. 290 (7): 4447–4463. doi:10.1074/jbc.M114.603977. PMC 4326849. PMID 25561724.
  33. ^ Nguyen P, Lee S, Lorang-Leins D, Trepel J, Smart DK (September 2014). "SIRT2 interacts with β-catenin to inhibit Wnt signaling output in response to radiation-induced stress". Molecular Cancer Research. 12 (9): 1244–1253. doi:10.1158/1541-7786.MCR-14-0223-T. PMC 4163538. PMID 24866770.
  34. ^ Xu Y, Li F, Lv L, Li T, Zhou X, Deng CX, et al. (July 2014). "Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase". Cancer Research. 74 (13): 3630–3642. doi:10.1158/0008-5472.CAN-13-3615. PMC 4303242. PMID 24786789.
  35. ^ Saxena M, Dykes SS, Malyarchuk S, Wang AE, Cardelli JA, Pruitt K (January 2015). "The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration". Oncogene. 34 (2): 188–198. doi:10.1038/onc.2013.549. PMC 4067478. PMID 24362520.
  36. ^ Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, Descamps O, et al. (November 2013). "Neuroprotective Sirtuin ratio reversed by ApoE4". Proceedings of the National Academy of Sciences of the United States of America. 110 (45): 18303–18308. Bibcode:2013PNAS..11018303T. doi:10.1073/pnas.1314145110. PMC 3831497. PMID 24145446.
  37. ^ van Leeuwen IM, Higgins M, Campbell J, McCarthy AR, Sachweh MC, Navarro AM, et al. (April 2013). "Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2". Molecular Cancer Therapeutics. 12 (4): 471–480. doi:10.1158/1535-7163.MCT-12-0904. PMID 23416275.
  38. ^ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, et al. (July 2011). "Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase". Molecular Cell. 43 (1): 33–44. doi:10.1016/j.molcel.2011.04.028. PMC 3962309. PMID 21726808.
  39. ^ Wang F, Tong Q (February 2009). "SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma". Molecular Biology of the Cell. 20 (3): 801–808. doi:10.1091/mbc.E08-06-0647. PMC 2633403. PMID 19037106.
  40. ^ Han Y, Jin YH, Kim YJ, Kang BY, Choi HJ, Kim DW, et al. (October 2008). "Acetylation of Sirt2 by p300 attenuates its deacetylase activity". Biochemical and Biophysical Research Communications. 375 (4): 576–580. doi:10.1016/j.bbrc.2008.08.042. PMID 18722353.
  41. ^ Jin YH, Kim YJ, Kim DW, Baek KH, Kang BY, Yeo CY, et al. (April 2008). "Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53". Biochemical and Biophysical Research Communications. 368 (3): 690–695. doi:10.1016/j.bbrc.2008.01.114. PMID 18249187.
  42. ^ Shimazu T, Horinouchi S, Yoshida M (February 2007). "Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing". The Journal of Biological Chemistry. 282 (7): 4470–4478. doi:10.1074/jbc.M609745200. PMID 17172643.

Further reading

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