Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT08MSHL)

DOT Name	Glutaminase liver isoform, mitochondrial (GLS2)
Synonyms	GLS; EC 3.5.1.2; L-glutaminase; L-glutamine amidohydrolase
Gene Name	GLS2
Related Disease	Acute lymphocytic leukaemia ( ) Gastric cancer ( ) Stomach cancer ( ) Adenoma ( ) Adult glioblastoma ( ) Alzheimer disease ( ) Astrocytoma ( ) Bladder cancer ( ) Breast neoplasm ( ) Childhood acute lymphoblastic leukemia ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Dementia ( ) Ependymoma ( ) Glioblastoma multiforme ( ) Glioma ( ) Hepatic encephalopathy ( ) Hepatocellular carcinoma ( ) Hypertension, pregnancy-induced ( ) Malignant glioma ( ) Neoplasm ( ) Pancreatic cancer ( ) Pancreatic tumour ( ) Transitional cell carcinoma ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Urothelial carcinoma ( ) Breast cancer ( ) Breast carcinoma ( ) Hypoglycemia ( ) Obesity ( ) Advanced cancer ( ) Colon adenocarcinoma ( ) Neuroblastoma ( ) Temporal lobe epilepsy ( ) Type-1/2 diabetes ( )
UniProt ID	GLSL_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4BQM; 5U0K
EC Number	3.5.1.2
Pfam ID	PF12796 ; PF17959 ; PF04960
Sequence	MRSMKALQKALSRAGSHCGRGGWGHPSRSPLLGGGVRHHLSEAAAQGRETPHSHQPQHQD HDSSESGMLSRLGDLLFYTIAEGQERIPIHKFTTALKATGLQTSDPRLRDCMSEMHRVVQ ESSSGGLLDRDLFRKCVSSNIVLLTQAFRKKFVIPDFEEFTGHVDRIFEDVKELTGGKVA AYIPQLAKSNPDLWGVSLCTVDGQRHSVGHTKIPFCLQSCVKPLTYAISISTLGTDYVHK FVGKEPSGLRYNKLSLNEEGIPHNPMVNAGAIVVSSLIKMDCNKAEKFDFVLQYLNKMAG NEYMGFSNATFQSEKETGDRNYAIGYYLKEKKCFPKGVDMMAALDLYFQLCSVEVTCESG SVMAATLANGGICPITGESVLSAEAVRNTLSLMHSCGMYDFSGQFAFHVGLPAKSAVSGA ILLVVPNVMGMMCLSPPLDKLGNSHRGTSFCQKLVSLFNFHNYDNLRHCARKLDPRREGA EIRNKTVVNLLFAAYSGDVSALRRFALSAMDMEQKDYDSRTALHVAAAEGHIEVVKFLIE ACKVNPFAKDRWGNIPLDDAVQFNHLEVVKLLQDYQDSYTLSETQAEAAAEALSKENLES MV
Function	Plays an important role in the regulation of glutamine catabolism. Promotes mitochondrial respiration and increases ATP generation in cells by catalyzing the synthesis of glutamate and alpha-ketoglutarate. Increases cellular anti-oxidant function via NADH and glutathione production. May play a role in preventing tumor proliferation.
Tissue Specificity	Highly expressed in liver. Expressed in brain and pancreas. Not observed in heart, placenta, lung, skeletal muscle and kidney. Expression is significantly reduced in hepatocellular carcinomas.
KEGG Pathway	Arginine biosynthesis (hsa00220 ) Alanine, aspartate and glutamate metabolism (hsa00250 ) D-Amino acid metabolism (hsa00470 ) Metabolic pathways (hsa01100 ) Glutamatergic sy.pse (hsa04724 ) GABAergic sy.pse (hsa04727 ) Proximal tubule bicarbo.te reclamation (hsa04964 ) MicroR.s in cancer (hsa05206 ) Central carbon metabolism in cancer (hsa05230 )
Reactome Pathway	TP53 Regulates Metabolic Genes (R-HSA-5628897 ) Glutamate and glutamine metabolism (R-HSA-8964539 ) Glutamate Neurotransmitter Release Cycle (R-HSA-210500 )

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute lymphocytic leukaemia	DISPX75S	Definitive	Biomarker	[1]
Gastric cancer	DISXGOUK	Definitive	Biomarker	[2]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[2]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Astrocytoma	DISL3V18	Strong	Altered Expression	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Dementia	DISXL1WY	Strong	Biomarker	[10]
Ependymoma	DISUMRNZ	Strong	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hepatic encephalopathy	DISEAKAN	Strong	Genetic Variation	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Hypertension, pregnancy-induced	DISHNU25	Strong	Genetic Variation	[14]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[16]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[16]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[15]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[15]
Hypoglycemia	DISRCKR7	moderate	Genetic Variation	[17]
Obesity	DIS47Y1K	moderate	Biomarker	[18]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[19]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[20]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[21]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[22]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[23]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Glutaminase liver isoform, mitochondrial (GLS2) affects the response to substance of Arsenic trioxide.	[38]
Hydrogen peroxide	DM1NG5W	Approved	Glutaminase liver isoform, mitochondrial (GLS2) affects the response to substance of Hydrogen peroxide.	[38]
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2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Glutaminase liver isoform, mitochondrial (GLS2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glutaminase liver isoform, mitochondrial (GLS2).	[35]
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13 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 Glutaminase liver isoform, mitochondrial (GLS2).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[29]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[25]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[30]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[31]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[32]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[36]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide increases the expression of Glutaminase liver isoform, mitochondrial (GLS2).	[37]
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⏷ Show the Full List of 13 Drug(s)

References

1	A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo.Cancer Res. 2018 Mar 15;78(6):1549-1560. doi: 10.1158/0008-5472.CAN-17-2106. Epub 2018 Jan 17.
2	RETRACTED: Physcion 8-O--glucopyranoside induced ferroptosis via regulating miR-103a-3p/GLS2 axis in gastric cancer.Life Sci. 2019 Nov 15;237:116893. doi: 10.1016/j.lfs.2019.116893. Epub 2019 Oct 10.
3	Comprehensive molecular analysis based on somatic copy number alterations in intramucosal colorectal neoplasias and early invasive colorectal cancers.Oncotarget. 2018 May 1;9(33):22895-22906. doi: 10.18632/oncotarget.25112. eCollection 2018 May 1.
4	Integrative cross-platform analyses identify enhanced heterotrophy as a metabolic hallmark in glioblastoma.Neuro Oncol. 2019 Feb 19;21(3):337-347. doi: 10.1093/neuonc/noy185.
5	Identifying potential GluN2B subunit containing N-Methyl-D-aspartate receptor inhibitors: an integrative in silico and molecular modeling approach.J Biomol Struct Dyn. 2020 Jun;38(9):2533-2545. doi: 10.1080/07391102.2019.1635530. Epub 2019 Jul 4.
6	Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients.Onco Targets Ther. 2018 Dec 4;11:8673-8684. doi: 10.2147/OTT.S176549. eCollection 2018.
7	Long non-coding RNA UCA1 promotes glutamine metabolism by targeting miR-16 in human bladder cancer.Jpn J Clin Oncol. 2015 Nov;45(11):1055-63. doi: 10.1093/jjco/hyv132. Epub 2015 Sep 14.
8	Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer.Cell Rep. 2019 Oct 1;29(1):76-88.e7. doi: 10.1016/j.celrep.2019.08.076.
9	Epigenetic silencing of glutaminase 2 in human liver and colon cancers.BMC Cancer. 2013 Dec 14;13:601. doi: 10.1186/1471-2407-13-601.
10	HIV-infected macrophages mediate neuronal apoptosis through mitochondrial glutaminase.J Neurochem. 2008 May;105(3):994-1005. doi: 10.1111/j.1471-4159.2007.05197.x. Epub 2007 Dec 18.
11	Relative expression of mRNAS coding for glutaminase isoforms in CNS tissues and CNS tumors.Neurochem Res. 2008 May;33(5):808-13. doi: 10.1007/s11064-007-9507-6. Epub 2007 Oct 17.
12	A genetic variant in the promoter of phosphate-activated glutaminase is associated with hepatic encephalopathy.J Intern Med. 2015 Sep;278(3):313-22. doi: 10.1111/joim.12374. Epub 2015 Jun 7.
13	Purification and characterization of l-glutaminase enzyme from camel liver: Enzymatic anticancer property.Int J Biol Macromol. 2020 May 1;150:1213-1222. doi: 10.1016/j.ijbiomac.2019.10.131. Epub 2019 Nov 16.
14	Obstetric and perinatal outcomes of singleton pregnancies conceived via assisted reproductive technology complicated by gestational diabetes mellitus: a prospective cohort study.BMC Pregnancy Childbirth. 2018 Dec 14;18(1):495. doi: 10.1186/s12884-018-2115-4.
15	GLS2 is protumorigenic in breast cancers.Oncogene. 2020 Jan;39(3):690-702. doi: 10.1038/s41388-019-1007-z. Epub 2019 Sep 20.
16	Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer.Proteomics. 2019 Nov;19(21-22):e1800451. doi: 10.1002/pmic.201800451. Epub 2019 Aug 1.
17	Asymmetric large-for-gestational-age infants of type 1 diabetic women: morbidity and abdominal growth.Am J Perinatol. 2010 Sep;27(8):603-10. doi: 10.1055/s-0030-1249362. Epub 2010 Mar 11.
18	Poor diet quality in pregnancy is associated with increased risk of excess fetal growth: a prospective multi-racial/ethnic cohort study.Int J Epidemiol. 2019 Apr 1;48(2):423-432. doi: 10.1093/ije/dyy285.
19	Multiomics Analysis Reveals that GLS and GLS2 Differentially Modulate the Clinical Outcomes of Cancer.J Clin Med. 2019 Mar 13;8(3):355. doi: 10.3390/jcm8030355.
20	p63 regulates glutaminase 2 expression.Cell Cycle. 2013 May 1;12(9):1395-405. doi: 10.4161/cc.24478. Epub 2013 Apr 10.
21	Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2.Oncotarget. 2015 Dec 1;6(38):40655-66. doi: 10.18632/oncotarget.5821.
22	Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy.Epilepsia. 2013 Feb;54(2):228-38. doi: 10.1111/epi.12008. Epub 2012 Nov 13.
23	Prevalence of newly detected diabetes in pregnancy in Qatar, using universal screening.PLoS One. 2018 Aug 3;13(8):e0201247. doi: 10.1371/journal.pone.0201247. eCollection 2018.
24	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.
25	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.
26	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
27	Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
28	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
29	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
30	Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
31	Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
32	Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
33	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
34	A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
35	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
36	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
37	Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer. Toxicol In Vitro. 2007 Dec;21(8):1513-29. doi: 10.1016/j.tiv.2007.06.021. Epub 2007 Jul 21.
38	Both GLS silencing and GLS2 overexpression synergize with oxidative stress against proliferation of glioma cells. J Mol Med (Berl). 2014 Mar;92(3):277-90. doi: 10.1007/s00109-013-1105-2. Epub 2013 Nov 26.