Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVU4G07)

• DOT Name: Guanylate-binding protein 2 (GBP2)
• Synonyms: EC 3.6.5.-; GTP-binding protein 2; GBP-2; HuGBP-2; Guanine nucleotide-binding protein 2; Interferon-induced guanylate-binding protein 2
• Gene Name: GBP2
• Related Disease:
  Neoplasm
  Adult T-cell leukemia/lymphoma
  Breast cancer
  Breast carcinoma
  Myocardial ischemia
  Non-insulin dependent diabetes
  Systemic lupus erythematosus
  Bacterial infection
  Colorectal carcinoma
  Squamous cell carcinoma
• UniProt ID: GBP2_HUMAN
• PDB ID: 6VKJ; 7E58; 7M1S
• EC Number: 3.6.5.-
• Pfam ID: PF02263 ; PF02841
• Sequence:
  MAPEINLPGPMSLIDNTKGQLVVNPEALKILSAITQPVVVVAIVGLYRTGKSYLMNKLAG
  KKNGFSLGSTVKSHTKGIWMWCVPHPKKPEHTLVLLDTEGLGDIEKGDNENDSWIFALAI
  LLSSTFVYNSMGTINQQAMDQLHYVTELTDRIKANSSPGNNSVDDSADFVSFFPAFVWTL
  RDFTLELEVDGEPITADDYLELSLKLRKGTDKKSKSFNDPRLCIRKFFPKRKCFVFDWPA
  PKKYLAHLEQLKEEELNPDFIEQVAEFCSYILSHSNVKTLSGGIPVNGPRLESLVLTYVN
  AISSGDLPCMENAVLALAQIENSAAVEKAIAHYEQQMGQKVQLPTETLQELLDLHRDSER
  EAIEVFMKNSFKDVDQMFQRKLGAQLEARRDDFCKQNSKASSDCCMALLQDIFGPLEEDV
  KQGTFSKPGGYRLFTQKLQELKNKYYQVPRKGIQAKEVLKKYLESKEDVADALLQTDQSL
  SEKEKAIEVERIKAESAEAAKKMLEEIQKKNEEMMEQKEKSYQEHVKQLTEKMERDRAQL
  MAEQEKTLALKLQEQERLLKEGFENESKRLQKDIWDIQMRSKSLEPICNIL
• Function: Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens. Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions, but the major reaction product is GDP. Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria. Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol. Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome. Confers protection to the protozoan pathogen Toxoplasma gondii. Independently of its GTPase activity, acts as an inhibitor of various viruses infectivity, such as HIV-1, Zika and influenza A viruses, by inhibiting FURIN-mediated maturation of viral envelope proteins.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Interferon alpha/beta signaling (R-HSA-909733)
  Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[6]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[8]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Guanylate-binding protein 2 (GBP2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanylate-binding protein 2 (GBP2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Guanylate-binding protein 2 (GBP2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Guanylate-binding protein 2 (GBP2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanylate-binding protein 2 (GBP2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Guanylate-binding protein 2 (GBP2).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Guanylate-binding protein 2 (GBP2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Guanylate-binding protein 2 (GBP2).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Guanylate-binding protein 2 (GBP2).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Guanylate-binding protein 2 (GBP2).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Guanylate-binding protein 2 (GBP2).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Guanylate-binding protein 2 (GBP2).	[20]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Guanylate-binding protein 2 (GBP2).	[21]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Guanylate-binding protein 2 (GBP2).	[22]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Guanylate-binding protein 2 (GBP2).	[23]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Guanylate-binding protein 2 (GBP2).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guanylate-binding protein 2 (GBP2).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Guanylate-binding protein 2 (GBP2).	[26]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Guanylate-binding protein 2 (GBP2).	[27]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Guanylate-binding protein 2 (GBP2).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Guanylate-binding protein 2 (GBP2).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Guanylate-binding protein 2 (GBP2).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Guanylate-binding protein 2 (GBP2).	[33]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Guanylate-binding protein 2 (GBP2).	[34]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Guanylate-binding protein 2 (GBP2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Guanylate-binding protein 2 (GBP2).	[31]

References

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• [2] Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One.Front Genet. 2019 Nov 8;10:1056. doi: 10.3389/fgene.2019.01056. eCollection 2019.
• [3] Correction: Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion.Cell Death Dis. 2018 Nov 13;9(11):1127. doi: 10.1038/s41419-018-1133-5.
• [4] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
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• [8] Guanylate-binding protein-2 inhibits colorectal cancer cell growth and increases the sensitivity to paclitaxel of paclitaxel-resistant colorectal cancer cells by interfering Wnt signaling.J Cell Biochem. 2020 Feb;121(2):1250-1259. doi: 10.1002/jcb.29358. Epub 2019 Sep 6.
• [9] Interferon-inducible guanylate binding protein (GBP)-2: a novel p53-regulated tumor marker in esophageal squamous cell carcinomas.Int J Cancer. 2009 Jan 15;124(2):272-9. doi: 10.1002/ijc.23944.
• [10] 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.
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• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [22] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [23] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [24] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [27] 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.
• [28] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [29] 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.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [32] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [34] 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.