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A conditional [[knockout mouse]] line, called ''Sirt2<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Sirt2 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4431586 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the [[Wellcome Trust Sanger Institute]].<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–342 | year = 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref> Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism. | journal = Genome Biol | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref>
A conditional [[knockout mouse]] line, called ''Sirt2<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Sirt2 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4431586 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the [[Wellcome Trust Sanger Institute]].<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–342 | year = 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref> Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism. | journal = Genome Biol | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref>
Twenty five tests were carried out on [[homozygous]] [[mutant]] adult mice, however no significant abnormalities were observed.<ref name="mgp_reference" />
Twenty five tests were carried out on [[homozygous]] [[mutant]] adult mice, however no significant abnormalities were observed.<ref name="mgp_reference" />

==Structure==

===Gene===
Human SIRT2 gene has 18 [[exons]] resides on chromosome 19 at q13.<ref name="entrez"/> For SIRT2, four different human splice variants are deposited in the GenBank sequence database.<ref name="pmid24177535">{{cite journal|last1=Rack|first1=JG|last2=VanLinden|first2=MR|last3=Lutter|first3=T|last4=Aasland|first4=R|last5=Ziegler|first5=M|title=Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform.|journal=Journal of molecular biology|date=17 April 2014|volume=426|issue=8|pages=1677-91|pmid=24177535}}</ref>

===Protein===
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.<ref name="entrez"/> Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A [[leucine]]-rich nuclear export signal (NES) within the [[N-terminus|N-terminal]] region of these two isoforms was identified.<ref name="pmid24177535"/> Since deletion of the NES led to nucleocytoplasmic distribution, it was suggested to mediate their cytosolic localization.<ref name="pmid17726514">{{cite journal|last1=North|first1=BJ|last2=Verdin|first2=E|title=Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis.|journal=PloS one|date=29 August 2007|volume=2|issue=8|pages=e784|pmid=17726514}}</ref>



== Selective ligands ==
== Selective ligands ==

Revision as of 02:55, 7 December 2015

Template:PBB NAD-dependent deacetylase sirtuin-2 is an enzyme that in humans is encoded by the SIRT2 gene.[1][2][3] 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. Recent study has shown the involvement of SIRT2 in the antiproliferative effects of resveratrol on primary cultures of human glioblastoma stem cells. SIRT2 could become a new therapeutic target.[4]


Function

Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.[3] Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system and gluconeogenesis.[5] 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.[6] In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo.[7] Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.[8]

Model organisms

The functions of human sirtuins have not yet been determined; however, model organisms have been used in the study of SIRT2 function. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.

A conditional knockout mouse line, called Sirt2tm1a(EUCOMM)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[13][14][15] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[9]

Structure

Gene

Human SIRT2 gene has 18 exons resides on chromosome 19 at q13.[3] For SIRT2, four different human splice variants are deposited in the GenBank sequence database.[17]

Protein

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.[3] 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 was identified.[17] Since deletion of the NES led to nucleocytoplasmic distribution, it was suggested to mediate their cytosolic localization.[18]


Selective ligands

Inhibitors

  • Benzamide compound # 64[19]
  • (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3[20]
  • 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM[21]

References

  1. ^ Afshar G, Murnane JP (Aug 1999). "Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2". Gene. 234 (1): 161–8. doi:10.1016/S0378-1119(99)00162-6. PMID 10393250.
  2. ^ Frye RA (Jul 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". Biochem Biophys Res Commun. 260 (1): 273–9. doi:10.1006/bbrc.1999.0897. PMID 10381378.
  3. ^ a b c d "Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)".
  4. ^ Sayd, S; Junier, MP; Chneiweiss, H (May 2014). "[SIRT2, a multi-talented deacetylase]". Medecine sciences : M/S. 30 (5): 532–6. PMID 24939540.
  5. ^ 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): 437–44. PMID 12620231.
  6. ^ Serrano, L; Martínez-Redondo, P; Marazuela-Duque, A; Vazquez, BN; Dooley, SJ; Voigt, P; Beck, DB; Kane-Goldsmith, N; Tong, Q; Rabanal, RM; Fondevila, D; Muñoz, P; Krüger, M; Tischfield, JA; Vaquero, A (15 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): 639–53. PMID 23468428.
  7. ^ Vempati, RK; Jayani, RS; Notani, D; Sengupta, A; Galande, S; Haldar, D (10 September 2010). "p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals". The Journal of biological chemistry. 285 (37): 28553–64. PMID 20587414.
  8. ^ Black, JC; Mosley, A; Kitada, T; Washburn, M; Carey, M (7 November 2008). "The SIRT2 deacetylase regulates autoacetylation of p300". Molecular cell. 32 (3): 449–55. PMID 18995842.
  9. ^ a b c Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
  10. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  11. ^ "International Knockout Mouse Consortium".
  12. ^ "Mouse Genome Informatics".
  13. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  14. ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  15. ^ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  16. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ a b Rack, JG; VanLinden, MR; Lutter, T; Aasland, R; Ziegler, M (17 April 2014). "Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform". Journal of molecular biology. 426 (8): 1677–91. PMID 24177535.
  18. ^ North, BJ; Verdin, E (29 August 2007). "Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis". PloS one. 2 (8): e784. PMID 17726514.
  19. ^ Cui H, Kamal Z, Ai T, Xu Y, More SS, Wilson DJ, Chen L (2014). "Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach". J. Med. Chem. doi:10.1021/jm500777s. PMID 25275824.
  20. ^ Fridén-Saxin M, Seifert T, Landergren MR, Suuronen T, Lahtela-Kakkonen M, Jarho EM, Luthman K (2012). "Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2-Selective Inhibitors". J. Med. Chem. 55 (16): 7104–13. doi:10.1021/jm3005288. PMC 3426190. PMID 22746324.
  21. ^ Suzuki T, Khan MN, Sawada H, Imai E, Itoh Y, Yamatsuta K, Tokuda N, Takeuchi J, Seko T, Nakagawa H, Miyata N (2012). "Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors". J. Med. Chem. 55 (12): 5760–73. doi:10.1021/jm3002108. PMID 22642300.

Further reading

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