Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
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Ligand Efficiency Plot
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Gene Expression
Gene Copy Number Variation
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SIRT2 (Q8IXJ6) - Overview - Molecular Target Synopsis

Protein


SIRT2, NAD-dependent protein deacetylase sirtuin-2
Enzyme Classification 3.5.1.-
UniProt Q8IXJ6

Also Known as SIR2_HUMAN, SIRT2, SIR2L, SIR2L2

NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors (PubMed:24177535, PubMed:12620231, PubMed:16648462, PubMed:18249187, PubMed:18332217, PubMed:18995842, PubMed:20587414, PubMed:21081649, PubMed:20543840, PubMed:22014574, PubMed:21726808, PubMed:21949390, PubMed:22771473, PubMed:23468428, PubMed:23908241, PubMed:24940000, PubMed:24769394, PubMed:24681946). Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by KMT5A leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression (PubMed:23468428). Deacetylates KMT5A modulating KMT5A chromatin localization during the mitotic stress response (PubMed:23468428). Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition. Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection (PubMed:23908241). During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates histone H4 at 'Lys-16' (H4K16ac) at the VEGFA promoter and thereby contributes to regulate expression of VEGFA, a key regulator of angiogenesis (PubMed:24940000). Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response t Interacts with CDC20, FOXO3 and FZR1. Associates with microtubules in primary cortical mature neurons (By similarity). Homotrimer. Isoform 1 and isoform 2 interact (via both phosphorylated, unphosphorylated, active or inactive forms) with HDAC6; the interaction is necessary for the complex to interact with alpha-tubulin, suggesting that these proteins belong to a large complex that deacetylates the cytoskeleton. Interacts with FOXO1; the interaction is disrupted upon serum-starvation or oxidative stress, leading to increased level of acetylated FOXO1 and induction of autophagy. Interacts with RELA; the interaction occurs in the cytoplasm and is increased in a TNF-alpha-dependent manner. Interacts with HOXA10; the interaction is direct. Interacts with YWHAB and YWHAG; the interactions occur in a AKT-dependent manner and increase SIRT2-dependent TP53 deacetylation. Interacts with MAPK1/ERK2 and MAPK3/ERK1; the interactions increase SIRT2 stability and deacetylation activity. Interacts (phosphorylated form) with KMT5A isoform 2; the interaction is direct, stimulates KMT5A-mediated methyltransferase activity on histone at 'Lys-20' (H4K20me1) and is increased in a H(2)O(2)-induced oxidative stress-dependent manner. Interacts with G6PD; the interaction is enhanced by H(2)O(2) treatment. Interacts with a G1/S-specific cyclin E-CDK2 complex. Interacts with AURKA, CDK5R1 (p35 form) and CDK5 and HIF1A. Isoform 1, isoform 2 and isoform 5 interact (via C-terminus region) with EP300 (PubMed:24177535). Interacts with the tRNA ligase SARS; recruited to the VEGFA promoter via interaction with SARS (PubMed:24940000). Interacts with BEX4; negatively regulates alpha-tubulin deacetylation by SIRT2 (PubMed:27512957).

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: SIRT2 is active in the following subcellular-locations: cell projection, centriole, centrosome, chromosome, cytoplasm, cytoskeleton, growth cone, microtubule organizing center, midbody, myelin membrane, nucleus, perikaryon, perinuclear region, spindle.
GO terms: SIRT2 is active in the following subcellular-locations: centriole, centrosome, chromatin silencing complex, chromosome, chromosome, cytoplasm, cytosol, glial cell projection, growth cone, juxtaparanode region of axon, lateral loop, meiotic spindle, microtubule, midbody, mitochondrion, mitotic spindle, myelin sheath, nuclear heterochromatin, nucleolus, nucleus, paranodal junction, paranode region of axon, perikaryon, perinuclear region of cytoplasm, plasma membrane, Schmidt-Lanterman incisure, spindle.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project SIRT2 has gain in 11 cell-lines, loss in 1 cell-lines and no signal in 993 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SNB_75, SK_OV_3, OVCAR_3

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: KLE, DMS 53, PANC-1

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HSMM, HUVEC

(see details)

3D Structures


For SIRT2 there are:
29 structures (52 chains) solved
23 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


SIRT2 has been screened with 1433 compounds (2137 bioactivities), 114 compounds have bioactivities that show binding affinity of <= 500nM (120 bioactivities). (see details)