Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR7NMRJ)

• DOT Name: Fructose-2,6-bisphosphatase TIGAR (TIGAR)
• Synonyms: EC 3.1.3.46; TP53-induced glycolysis and apoptosis regulator; TP53-induced glycolysis regulatory phosphatase
• Gene Name: TIGAR
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adult glioblastoma
  Adult lymphoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Alzheimer disease
  Breast carcinoma
  Cerebral infarction
  Cerebral palsy
  Chronic pancreatitis
  Clear cell renal carcinoma
  Colonic neoplasm
  Dementia
  Epilepsy
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Hepatocellular carcinoma
  Intervertebral disc degeneration
  Isolated cleft palate
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Pancreas disorder
  Pediatric lymphoma
  Retinoblastoma
  Small lymphocytic lymphoma
  Stroke
  T-cell lymphoma
  Ulcerative colitis
  Carcinoma of liver and intrahepatic biliary tract
  Hypoglycemia
  Liver cancer
  Primary cutaneous T-cell lymphoma
  Colorectal carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Lewy body dementia
  Motor neurone disease
  Nasopharyngeal carcinoma
  Pancreatitis
  Parkinson disease
  Stomach cancer
• UniProt ID: TIGAR_HUMAN
• PDB ID: 3DCY
• EC Number: 3.1.3.46
• Pfam ID: PF00300
• Sequence:
  MARFALTVVRHGETRFNKEKIIQGQGVDEPLSETGFKQAAAAGIFLNNVKFTHAFSSDLM
  RTKQTMHGILERSKFCKDMTVKYDSRLRERKYGVVEGKALSELRAMAKAAREECPVFTPP
  GGETLDQVKMRGIDFFEFLCQLILKEADQKEQFSQGSPSNCLETSLAEIFPLGKNHSSKV
  NSDSGIPGLAASVLVVSHGAYMRSLFDYFLTDLKCSLPATLSRSELMSVTPNTGMSLFII
  NFEEGREVKPTVQCICMNLQDHLNGLTETR
• Function: Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate. Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production. Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death. Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity. In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3. Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage. Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation. Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions. Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner. Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses. Involved in intestinal tumor progression.
• Tissue Specificity: Expressed in the brain . Expressed in breast tumors . Expressed in glioblastomas .
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Metabolic pathways (hsa01100)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway: TP53 Regulates Metabolic Genes (R-HSA-5628897)
• BioCyc Pathway: MetaCyc:HS01277-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[3]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[8]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[9]
Chronic pancreatitis	DISBUOMJ	Strong	Genetic Variation	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[10]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[11]
Dementia	DISXL1WY	Strong	Altered Expression	[6]
Epilepsy	DISBB28L	Strong	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[13]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[14]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[16]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[9]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Lymphoma	DISN6V4S	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[20]
Pancreas disorder	DISDH7NI	Strong	Biomarker	[21]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[3]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[22]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[23]
Stroke	DISX6UHX	Strong	Biomarker	[24]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[3]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[11]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Posttranslational Modification	[25]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[26]
Liver cancer	DISDE4BI	moderate	Posttranslational Modification	[25]
Primary cutaneous T-cell lymphoma	DIS35WVW	Disputed	Altered Expression	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[28]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[29]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[2]
Lewy body dementia	DISAE66J	Limited	Biomarker	[30]
Motor neurone disease	DISUHWUI	Limited	Biomarker	[30]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[31]
Pancreatitis	DIS0IJEF	Limited	Biomarker	[21]
Parkinson disease	DISQVHKL	Limited	Biomarker	[30]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[29]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[38]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[39]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[40]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[41]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[42]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[43]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[44]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[45]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[46]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[47]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[44]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[44]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[44]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[48]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[44]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[48]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[50]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[46]
DZNep	DM0JXBK	Investigative	DZNep decreases the expression of Fructose-2,6-bisphosphatase TIGAR (TIGAR).	[51]

References

• [1] TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia.J Hematol Oncol. 2016 Nov 25;9(1):128. doi: 10.1186/s13045-016-0360-4.
• [2] TIGAR promotes growth, survival and metastasis through oxidation resistance and AKT activation in glioblastoma.Oncol Lett. 2019 Sep;18(3):2509-2517. doi: 10.3892/ol.2019.10574. Epub 2019 Jul 5.
• [3] The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30(II) and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.Virology. 2018 Jul;520:39-58. doi: 10.1016/j.virol.2018.05.007. Epub 2018 May 26.
• [4] The human T-cell leukemia virus type-1 p30(II) protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis.Virology. 2018 May;518:103-115. doi: 10.1016/j.virol.2018.02.010. Epub 2018 Feb 20.
• [5] TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells.Acta Pharmacol Sin. 2019 Jan;40(1):111-121. doi: 10.1038/s41401-018-0001-2. Epub 2018 May 16.
• [6] Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease [corrected].PLoS One. 2013 Jul 5;8(7):e68361. doi: 10.1371/journal.pone.0068361. Print 2013.
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• [16] TIGAR impedes compression-induced intervertebral disc degeneration by suppressing nucleus pulposus cell apoptosis and autophagy.J Cell Physiol. 2020 Feb;235(2):1780-1794. doi: 10.1002/jcp.29097. Epub 2019 Jul 17.
• [17] High expression of synthesis of cytochrome c oxidase 2 and TP53-induced glycolysis and apoptosis regulator can predict poor prognosis in human lung adenocarcinoma.Hum Pathol. 2018 Jul;77:54-62. doi: 10.1016/j.humpath.2017.12.029. Epub 2018 Apr 7.
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• [19] Knockdown of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Sensitizes Glioma Cells to Hypoxia, Irradiation and Temozolomide.Int J Mol Sci. 2019 Mar 1;20(5):1061. doi: 10.3390/ijms20051061.
• [20] Loss of TIGAR Induces Oxidative Stress and Meiotic Defects in Oocytes from Obese Mice.Mol Cell Proteomics. 2018 Jul;17(7):1354-1364. doi: 10.1074/mcp.RA118.000620. Epub 2018 May 18.
• [21] Pancreatitis: TIGAR-O Version 2 Risk/Etiology Checklist With Topic Reviews, Updates, and Use Primers.Clin Transl Gastroenterol. 2019 Jun;10(6):e00027. doi: 10.14309/ctg.0000000000000027.
• [22] TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex.Br J Cancer. 2012 Jul 24;107(3):516-26. doi: 10.1038/bjc.2012.260. Epub 2012 Jul 10.
• [23] TP53-induced glycolysis and apoptosis regulator protects from spontaneous apoptosis and predicts poor prognosis in chronic lymphocytic leukemia.Leuk Res. 2016 Nov;50:72-77. doi: 10.1016/j.leukres.2016.09.013. Epub 2016 Sep 15.
• [24] TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury.Free Radic Biol Med. 2019 Jun;137:13-23. doi: 10.1016/j.freeradbiomed.2019.04.002. Epub 2019 Apr 9.
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• [26] Melatonin ameliorates hypoglycemic stress-induced brain endothelial tight junction injury by inhibiting protein nitration of TP53-induced glycolysis and apoptosis regulator.J Pineal Res. 2017 Nov;63(4):e12440. doi: 10.1111/jpi.12440. Epub 2017 Sep 6.
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• [30] TIGAR inclusion pathology is specific for Lewy body diseases.Brain Res. 2019 Mar 1;1706:218-223. doi: 10.1016/j.brainres.2018.09.032. Epub 2018 Sep 26.
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