Sirtuin 2
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SIRT2
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| Location (UCSC) | Chr 19: 38.88 – 38.9 Mb | Chr 7: 28.47 – 28.49 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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NAD-dependent deacetylase sirtuin 2 is an
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
Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.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
Gene
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
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
Inhibitors
- 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
Metabolic actions
SIRT2 suppresses inflammatory responses in mice through
erythrocytes.[21]
Neurodegeneration
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
Metabolic actions
Several SIRT2
FOXO3a, and thereby reduces ROS
levels.
Cell cycle regulation
Although preferentially cytosolic, SIRT2 transiently shuttles to the
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
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
SIRT2 has been shown to
interact
with:
- α-tubulin,[31]
- TUG,[32]
- β-catenin,[33]
- PGAM2,[34]
- TIAM1,[35]
- ApoE4,[36]
- p53,[37]
- PEPCK,[38]
- FOXO1,[39]
- p300,[40]
- 14-3-3 protein,[41]
- and
- CBP.[42]
References
- ^ a b c ENSG00000068903 GRCh38: Ensembl release 89: ENSG00000283100, ENSG00000068903 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015149 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 10393250.
- PMID 10381378.
- ^ a b c d "Entrez Gene: SIRT2 sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)".
- PMID 24939540.
- PMID 21791548.
- PMID 12620231.
- PMID 23468428.
- PMID 20587414.
- PMID 18995842.
- ^ PMID 24177535.
- ^ PMID 17726514.
- PMID 25275824.
- PMID 22746324.
- PMID 22642300.
- PMID 26538315.
- ^ PMID 24769394.
- S2CID 84493360.
- PMID 20378838.
- PMID 25608039.
- PMID 16648462.
- S2CID 21357335.
- PMID 12697818.
- PMID 22014574.
- PMID 26977881.
- ^ PMID 27586085.
- PMID 26209361.
- PMID 25561724.
- PMID 24866770.
- PMID 24786789.
- PMID 24362520.
- PMID 24145446.
- PMID 23416275.
- PMID 21726808.
- PMID 19037106.
- PMID 18722353.
- PMID 18249187.
- PMID 17172643.
Further reading
- Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–74. PMID 8125298.
- Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. PMID 8619474.
- Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–58. PMID 9110174.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. PMID 9373149.
- Frye RA (Jul 2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochemical and Biophysical Research Communications. 273 (2): 793–98. PMID 10873683.
- Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL (Aug 2000). "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America. 97 (17): 9543–48. PMID 10931946.
- Finnin MS, Donigian JR, Pavletich NP (Jul 2001). "Structure of the histone deacetylase SIRT2". Nature Structural Biology. 8 (7): 621–25. S2CID 27800665.
- Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL (Oct 2001). "Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening". The Journal of Biological Chemistry. 276 (42): 38837–43. PMID 11483616.
- Borra MT, O'Neill FJ, Jackson MD, Marshall B, Verdin E, Foltz KR, Denu JM (Apr 2002). "Conserved enzymatic production and biological effect of O-acetyl-ADP-ribose by silent information regulator 2-like NAD+-dependent deacetylases". The Journal of Biological Chemistry. 277 (15): 12632–41. PMID 11812793.
- De Smet C, Nishimori H, Furnari FB, Bögler O, Huang HJ, Cavenee WK (May 2002). "A novel seven transmembrane receptor induced during the early steps of astrocyte differentiation identified by differential expression". Journal of Neurochemistry. 81 (3): 575–88. S2CID 23925334.
- North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (Feb 2003). "The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase". Molecular Cell. 11 (2): 437–44. PMID 12620231.
- 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. PMID 12697818.
- Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, Sartorelli V (Jul 2003). "Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state". Molecular Cell. 12 (1): 51–62. PMID 12887892.
- Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, Watanabe T, Ohama E, Tahimic CG, Kurimasa A, Oshimura M (Sep 2003). "Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene" (PDF). Biochemical and Biophysical Research Communications. 309 (3): 558–66. PMID 12963026.
- van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM (Jul 2004). "FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1)". The Journal of Biological Chemistry. 279 (28): 28873–79. PMID 15126506.
- Bae NS, Swanson MJ, Vassilev A, Howard BH (Jun 2004). "Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10". Journal of Biochemistry. 135 (6): 695–700. PMID 15213244.
- de Oliveira RM, Sarkander J, Kazantsev AG, Outeiro TF (2012). "SIRT2 as a Therapeutic Target for Age-Related Disorders". Frontiers in Pharmacology. 3: 82. PMID 22563317.
External links
- 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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