Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5S0J23)

DOT Name NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4)
Synonyms
EC 2.3.1.-; NAD-dependent ADP-ribosyltransferase sirtuin-4; EC 2.4.2.-; NAD-dependent protein biotinylase sirtuin-4; EC 2.3.1.-; NAD-dependent protein deacetylase sirtuin-4; EC 2.3.1.286; Regulatory protein SIR2 homolog 4; SIR2-like protein 4
Gene Name SIRT4
Related Disease
Breast cancer ( )
Breast carcinoma ( )
Coronary heart disease ( )
Non-alcoholic fatty liver disease ( )
Adenocarcinoma ( )
B-cell neoplasm ( )
Burkitt lymphoma ( )
Colorectal carcinoma ( )
Cytochrome-c oxidase deficiency disease ( )
Diabetic kidney disease ( )
Endometrial cancer ( )
Endometrial carcinoma ( )
Esophageal squamous cell carcinoma ( )
Estrogen-receptor positive breast cancer ( )
Head-neck squamous cell carcinoma ( )
Hyperinsulinemia ( )
Lung cancer ( )
Lung carcinoma ( )
Lung neoplasm ( )
Metabolic disorder ( )
Myocardial fibrosis ( )
Myocardial infarction ( )
Myocardial ischemia ( )
Neoplasm ( )
Non-insulin dependent diabetes ( )
Non-small-cell lung cancer ( )
Obesity ( )
Thyroid cancer ( )
Thyroid gland carcinoma ( )
Thyroid tumor ( )
Tubular aggregate myopathy ( )
Type-1/2 diabetes ( )
Advanced cancer ( )
Diabetic retinopathy ( )
Hepatocellular carcinoma ( )
Metastatic malignant neoplasm ( )
Pancreatic cancer ( )
Retinopathy ( )
Carcinoma of liver and intrahepatic biliary tract ( )
Coronary atherosclerosis ( )
Liver cancer ( )
Neuroblastoma ( )
Squamous cell carcinoma ( )
UniProt ID
SIR4_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
2.3.1.-; 2.3.1.286; 2.4.2.-
Pfam ID
PF02146
Sequence
MKMSFALTFRSAKGRWIANPSQPCSKASIGLFVPASPPLDPEKVKELQRFITLSKRLLVM
TGAGISTESGIPDYRSEKVGLYARTDRRPIQHGDFVRSAPIRQRYWARNFVGWPQFSSHQ
PNPAHWALSTWEKLGKLYWLVTQNVDALHTKAGSRRLTELHGCMDRVLCLDCGEQTPRGV
LQERFQVLNPTWSAEAHGLAPDGDVFLSEEQVRSFQVPTCVQCGGHLKPDVVFFGDTVNP
DKVDFVHKRVKEADSLLVVGSSLQVYSGYRFILTAWEKKLPIAILNIGPTRSDDLACLKL
NSRCGELLPLIDPC
Function
Acts as a NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase. Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner. Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity. Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest. In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation. Acts as a tumor suppressor. Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis. Does not seem to deacetylate PC. Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels. Down-regulates insulin secretion.
Tissue Specificity
Detected in vascular smooth muscle and striated muscle. Detected in insulin-producing beta-cells in pancreas islets of Langerhans (at protein level). Widely expressed. Weakly expressed in leukocytes and fetal thymus.
KEGG Pathway
Nicoti.te and nicoti.mide metabolism (hsa00760 )
Metabolic pathways (hsa01100 )
Reactome Pathway
Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201 )
BioCyc Pathway
MetaCyc:ENSG00000089163-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Breast cancer DIS7DPX1 Definitive Biomarker [1]
Breast carcinoma DIS2UE88 Definitive Biomarker [1]
Coronary heart disease DIS5OIP1 Definitive Altered Expression [2]
Non-alcoholic fatty liver disease DISDG1NL Definitive Altered Expression [2]
Adenocarcinoma DIS3IHTY Strong Altered Expression [3]
B-cell neoplasm DISVY326 Strong Biomarker [4]
Burkitt lymphoma DIS9D5XU Strong Biomarker [4]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [5]
Cytochrome-c oxidase deficiency disease DISK7N3G Strong Biomarker [6]
Diabetic kidney disease DISJMWEY Strong Biomarker [7]
Endometrial cancer DISW0LMR Strong Altered Expression [8]
Endometrial carcinoma DISXR5CY Strong Altered Expression [8]
Esophageal squamous cell carcinoma DIS5N2GV Strong Biomarker [9]
Estrogen-receptor positive breast cancer DIS1H502 Strong Biomarker [1]
Head-neck squamous cell carcinoma DISF7P24 Strong Biomarker [10]
Hyperinsulinemia DISIDWT6 Strong Genetic Variation [11]
Lung cancer DISCM4YA Strong Biomarker [3]
Lung carcinoma DISTR26C Strong Biomarker [3]
Lung neoplasm DISVARNB Strong Biomarker [12]
Metabolic disorder DIS71G5H Strong Biomarker [13]
Myocardial fibrosis DISMOLYU Strong Biomarker [14]
Myocardial infarction DIS655KI Strong Altered Expression [15]
Myocardial ischemia DISFTVXF Strong Altered Expression [16]
Neoplasm DISZKGEW Strong Biomarker [17]
Non-insulin dependent diabetes DISK1O5Z Strong Biomarker [18]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [3]
Obesity DIS47Y1K Strong Altered Expression [19]
Thyroid cancer DIS3VLDH Strong Altered Expression [20]
Thyroid gland carcinoma DISMNGZ0 Strong Altered Expression [20]
Thyroid tumor DISLVKMD Strong Altered Expression [20]
Tubular aggregate myopathy DISC11WH Strong Biomarker [21]
Type-1/2 diabetes DISIUHAP Strong Genetic Variation [11]
Advanced cancer DISAT1Z9 moderate Biomarker [22]
Diabetic retinopathy DISHGUJM moderate Altered Expression [18]
Hepatocellular carcinoma DIS0J828 moderate Biomarker [23]
Metastatic malignant neoplasm DIS86UK6 moderate Altered Expression [24]
Pancreatic cancer DISJC981 moderate Biomarker [25]
Retinopathy DISB4B0F moderate Biomarker [18]
Carcinoma of liver and intrahepatic biliary tract DIS8WA0W Limited Biomarker [26]
Coronary atherosclerosis DISKNDYU Limited Altered Expression [2]
Liver cancer DISDE4BI Limited Biomarker [26]
Neuroblastoma DISVZBI4 Limited Biomarker [27]
Squamous cell carcinoma DISQVIFL Limited Altered Expression [28]
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⏷ Show the Full List of 43 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [29]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [38]
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10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [30]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [31]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [32]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [33]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [34]
Decitabine DMQL8XJ Approved Decitabine affects the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [35]
Vitamin B3 DMQVRZH Approved Vitamin B3 increases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [36]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone increases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [37]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [39]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of NAD-dependent protein lipoamidase sirtuin-4, mitochondrial (SIRT4). [40]
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⏷ Show the Full List of 10 Drug(s)

References

1 SIRT4 enhances the sensitivity of ER-positive breast cancer to tamoxifen by inhibiting the IL-6/STAT3 signal pathway.Cancer Med. 2019 Nov;8(16):7086-7097. doi: 10.1002/cam4.2557. Epub 2019 Oct 1.
2 Corrigendum to "Circulating Levels of Sirtuin 4, a Potential Marker of Oxidative Metabolism, Related to Coronary Artery Disease in Obese Patients Suffering from NAFLD, with Normal or Slightly Increased Liver Enzymes".Oxid Med Cell Longev. 2018 Aug 13;2018:6357164. doi: 10.1155/2018/6357164. eCollection 2018.
3 SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway.Oncogene. 2017 May 11;36(19):2724-2736. doi: 10.1038/onc.2016.425. Epub 2016 Dec 12.
4 SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma.J Biol Chem. 2014 Feb 14;289(7):4135-44. doi: 10.1074/jbc.M113.525949. Epub 2013 Dec 24.
5 Knockout of SIRT4 decreases chemosensitivity to 5-FU in colorectal cancer cells.Oncol Lett. 2018 Aug;16(2):1675-1681. doi: 10.3892/ol.2018.8850. Epub 2018 May 31.
6 Alterations of sirtuins in mitochondrial cytochrome c-oxidase deficiency.PLoS One. 2017 Oct 23;12(10):e0186517. doi: 10.1371/journal.pone.0186517. eCollection 2017.
7 SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis.Exp Ther Med. 2017 Jan;13(1):342-348. doi: 10.3892/etm.2016.3938. Epub 2016 Nov 30.
8 Assessing sirtuin expression in endometrial carcinoma and non-neoplastic endometrium.Oncotarget. 2016 Jan 12;7(2):1144-54. doi: 10.18632/oncotarget.6691.
9 Downregulation of SIRT4 Expression Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma.Oncology. 2016;90(6):347-55. doi: 10.1159/000445323. Epub 2016 Apr 16.
10 Loss of Mitochondrial Tumor Suppressor Genes Expression Is Associated with Unfavorable Clinical Outcome in Head and Neck Squamous Cell Carcinoma: Data from Retrospective Study.PLoS One. 2016 Jan 19;11(1):e0146948. doi: 10.1371/journal.pone.0146948. eCollection 2016.
11 Mitochondrial Function, Metabolic Regulation, and Human Disease Viewed through the Prism of Sirtuin 4 (SIRT4) Functions.J Proteome Res. 2019 May 3;18(5):1929-1938. doi: 10.1021/acs.jproteome.9b00086. Epub 2019 Apr 8.
12 SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism.Cancer Cell. 2013 Apr 15;23(4):450-63. doi: 10.1016/j.ccr.2013.02.024. Epub 2013 Apr 4.
13 SIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise.Front Physiol. 2019 Aug 9;10:1006. doi: 10.3389/fphys.2019.01006. eCollection 2019.
14 SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity.Eur Heart J. 2017 May 7;38(18):1389-1398. doi: 10.1093/eurheartj/ehw138.
15 Amelioration of myocardial ischemia-reperfusion injury by SIRT4 involves mitochondrial protection and reduced apoptosis.Biochem Biophys Res Commun. 2018 Jul 7;502(1):15-21. doi: 10.1016/j.bbrc.2018.05.113. Epub 2018 May 24.
16 A ternary complex model of Sirtuin4-NAD(+)-Glutamate dehydrogenase.Comput Biol Chem. 2018 Jun;74:94-104. doi: 10.1016/j.compbiolchem.2018.03.006. Epub 2018 Mar 10.
17 Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest.Oncol Lett. 2019 Feb;17(2):2171-2176. doi: 10.3892/ol.2018.9877. Epub 2018 Dec 28.
18 Differential expressions of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells from patients with type 2 diabetic retinopathy.Arch Physiol Biochem. 2020 Oct;126(4):363-368. doi: 10.1080/13813455.2018.1543328. Epub 2018 Dec 20.
19 Adherence to the Mediterranean Diet and Circulating Levels of Sirtuin 4 in Obese Patients: A Novel Association.Oxid Med Cell Longev. 2017;2017:6101254. doi: 10.1155/2017/6101254. Epub 2017 Jun 15.
20 SIRT4 inhibits the proliferation, migration, and invasion abilities of thyroid cancer cells by inhibiting glutamine metabolism.Onco Targets Ther. 2019 Mar 28;12:2397-2408. doi: 10.2147/OTT.S189536. eCollection 2019.
21 SIRT4 silencing in tumor-associated macrophages promotes HCC development via PPAR signalling-mediated alternative activation of macrophages.J Exp Clin Cancer Res. 2019 Nov 19;38(1):469. doi: 10.1186/s13046-019-1456-9.
22 Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer.Onco Targets Ther. 2018 Jun 11;11:3395-3400. doi: 10.2147/OTT.S157724. eCollection 2018.
23 Sirtuin 4 Depletion Promotes Hepatocellular Carcinoma Tumorigenesis Through Regulating Adenosine-Monophosphate-Activated Protein Kinase Alpha/Mammalian Target of Rapamycin Axis in Mice.Hepatology. 2019 Apr;69(4):1614-1631. doi: 10.1002/hep.30421. Epub 2019 Mar 12.
24 Tumour-suppressive function of SIRT4 in human colorectal cancer.Br J Cancer. 2015 Jul 28;113(3):492-9. doi: 10.1038/bjc.2015.226. Epub 2015 Jun 18.
25 UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer.Cancer Lett. 2019 Jun 28;452:226-236. doi: 10.1016/j.canlet.2019.03.024. Epub 2019 Mar 22.
26 Facilitation of liver cancer SMCC7721 cell aging by sirtuin 4 via inhibiting JAK2/STAT3 signal pathway.Eur Rev Med Pharmacol Sci. 2017 Mar;21(6):1248-1253.
27 Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage.Cancer Manag Res. 2018 Nov 9;10:5591-5603. doi: 10.2147/CMAR.S172509. eCollection 2018.
28 Associations of sirtuins with clinicopathological parameters and prognosis in non-small cell lung cancer.Cancer Manag Res. 2018 Sep 10;10:3341-3356. doi: 10.2147/CMAR.S166946. eCollection 2018.
29 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
30 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
31 Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
32 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
33 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
34 SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells. Antioxid Redox Signal. 2016 Feb 20;24(6):329-43. doi: 10.1089/ars.2015.6331. Epub 2015 Nov 10.
35 Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
36 Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PLoS One. 2012;7(7):e42276. doi: 10.1371/journal.pone.0042276. Epub 2012 Jul 31.
37 Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
38 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
39 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
40 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.