Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT28VBVK)

• DOT Name: Ubiquitin-like-conjugating enzyme ATG3 (ATG3)
• Synonyms: EC 2.3.2.-; Autophagy-related protein 3; APG3-like; hApg3; Protein PC3-96
• Gene Name: ATG3
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Childhood myelodysplastic syndrome
  Colon cancer
  Colon carcinoma
  Endometriosis
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Neoplasm
  Scrub typhus
  Tuberculosis
  Non-small-cell lung cancer
• UniProt ID: ATG3_HUMAN
• PDB ID: 4NAW; 8AFI; 8FKM
• EC Number: 2.3.2.-
• Pfam ID: PF03987
• Sequence:
  MQNVINTVKGKALEVAEYLTPVLKESKFKETGVITPEEFVAAGDHLVHHCPTWQWATGEE
  LKVKAYLPTGKQFLVTKNVPCYKRCKQMEYSDELEAIIEEDDGDGGWVDTYHNTGITGIT
  EAVKEITLENKDNIRLQDCSALCEEEEDEDEGEAADMEEYEESGLLETDEATLDTRKIVE
  ACKAKTDAGGEDAILQTRTYDLYITYDKYYQTPRLWLFGYDEQRQPLTVEHMYEDISQDH
  VKKTVTIENHPHLPPPPMCSVHPCRHAEVMKKIIETVAEGGGELGVHMYLLIFLKFVQAV
  IPTIEYDYTRHFTM
• Function: E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane resulting in membrane-bound ATG8-like proteins which is one of the key steps in the development of autophagic isolation membranes during autophagosome formation. Cycles back and forth between binding to ATG7 for loading with the ATG8-like proteins and binding to E3 enzyme, composed of ATG12, ATG5 and ATG16L1 to promote ATG8-like proteins lipidation. Also plays a role as a membrane curvature sensor that facilitates LC3/GABARAP lipidation by sensing local membrane stress associated with lipid-packing defects as occurs with high molar proportions of conical lipids or strident membrane curvature. Interacts with negatively-charged membranes promoting membrane tethering and enhancing LC3/GABARAP lipidation. Also acts as an autocatalytic E2-like enzyme by catalyzing the conjugation of ATG12 to itself in an ATG7-dependent manner, this complex thus formed, plays a role in mitochondrial homeostasis but not in autophagy. ATG12-ATG3 conjugation promotes late endosome to lysosome trafficking and basal autophagosome maturation via its interaction with PDCD6IP. ATG12-ATG3 conjugate is also formed upon viccina virus infection, leading to the disruption the cellular autophagy which is not necessary for vaccinia survival and proliferation. Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway.
• Tissue Specificity: Widely expressed, with a highest expression in heart, skeletal muscle, kidney, liver and placenta.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Endometriosis	DISX1AG8	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Altered Expression	[8]
Leukemia	DISNAKFL	Strong	Altered Expression	[8]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Scrub typhus	DISRXONX	Strong	Genetic Variation	[10]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[11]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[12]

21 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 Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[18]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[16]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[16]
Artesunate	DMR27C8	Approved	Artesunate increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[19]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[16]
Cantharidin	DMBP5N3	Approved	Cantharidin increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[20]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[21]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[22]
GSK618334	DMJPXZ4	Phase 1	GSK618334 increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[23]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[26]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[27]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[28]
Galangin	DM5TQ2O	Investigative	Galangin increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[29]
Syringic Acid	DM802V7	Investigative	Syringic Acid increases the expression of Ubiquitin-like-conjugating enzyme ATG3 (ATG3).	[30]

References

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• [3] Lentiviral vector-mediate ATG3 overexpression inhibits growth and promotes apoptosis of human SKM-1 cells.Mol Biol Rep. 2014;41(4):2093-9. doi: 10.1007/s11033-014-3058-0. Epub 2014 Jan 14.
• [4] ATG3, a Target of miR-431-5p, Promotes Proliferation and Invasion of Colon Cancer via Promoting Autophagy.Cancer Manag Res. 2019 Dec 9;11:10275-10285. doi: 10.2147/CMAR.S226828. eCollection 2019.
• [5] EPHA3 enhances macrophage autophagy and apoptosis by disrupting the mTOR signaling pathway in mice with endometriosis.Biosci Rep. 2019 Jul 30;39(7):BSR20182274. doi: 10.1042/BSR20182274. Print 2019 Jul 31.
• [6] Upregulation of the lncRNA Meg3 induces autophagy to inhibit tumorigenesis and progression of epithelial ovarian carcinoma by regulating activity of ATG3.Oncotarget. 2017 May 9;8(19):31714-31725. doi: 10.18632/oncotarget.15955.
• [7] LncRNA NEAT1 promotes autophagy via regulating miR-204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma.J Cell Physiol. 2020 Apr;235(4):3402-3413. doi: 10.1002/jcp.29230. Epub 2019 Sep 23.
• [8] Atg3 Overexpression Enhances Bortezomib-Induced Cell Death in SKM-1 Cell.PLoS One. 2016 Jul 8;11(7):e0158761. doi: 10.1371/journal.pone.0158761. eCollection 2016.
• [9] Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.PLoS One. 2012;7(10):e48532. doi: 10.1371/journal.pone.0048532. Epub 2012 Oct 31.
• [10] Active escape of Orientia tsutsugamushi from cellular autophagy.Infect Immun. 2013 Feb;81(2):552-9. doi: 10.1128/IAI.00861-12. Epub 2012 Dec 10.
• [11] Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells.PLoS Pathog. 2018 Jan 4;14(1):e1006790. doi: 10.1371/journal.ppat.1006790. eCollection 2018 Jan.
• [12] Long Noncoding RNA KCNQ1OT1 Promotes the Progression of Non-Small Cell Lung Cancer via Regulating miR-204-5p/ATG3 Axis.Onco Targets Ther. 2019 Dec 10;12:10787-10797. doi: 10.2147/OTT.S226044. eCollection 2019.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy. Oxid Med Cell Longev. 2018 Mar 18;2018:1482795. doi: 10.1155/2018/1482795. eCollection 2018.
• [16] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [17] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [18] 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.
• [19] Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 2019 Jan;109:2043-2053. doi: 10.1016/j.biopha.2018.11.030. Epub 2018 Nov 26.
• [20] Endoplasmic reticulum stress contributes to autophagy and apoptosis in cantharidin-induced nephrotoxicity. Food Chem Toxicol. 2022 May;163:112986. doi: 10.1016/j.fct.2022.112986. Epub 2022 Apr 6.
• [21] TNF enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett. 2021 May 15;342:73-84. doi: 10.1016/j.toxlet.2021.02.009. Epub 2021 Feb 17.
• [22] Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. Br J Nutr. 2013 Dec;110(12):2150-5.
• [23] FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells. Toxicol Lett. 2015 Jul 2;236(1):43-59. doi: 10.1016/j.toxlet.2015.04.015. Epub 2015 May 1.
• [24] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [25] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [26] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [27] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [28] Sodium Butyrate Induces Endoplasmic Reticulum Stress and Autophagy in Colorectal Cells: Implications for Apoptosis. PLoS One. 2016 Jan 19;11(1):e0147218. doi: 10.1371/journal.pone.0147218. eCollection 2016.
• [29] Galangin suppresses HepG2 cell proliferation by activating the TGF- receptor/Smad pathway. Toxicology. 2014 Dec 4;326:9-17. doi: 10.1016/j.tox.2014.09.010. Epub 2014 Sep 28.
• [30] In vitro and in vivo anticancer effects of syringic acid on colorectal cancer: Possible mechanistic view. Chem Biol Interact. 2021 Mar 1;337:109337. doi: 10.1016/j.cbi.2020.109337. Epub 2021 Feb 4.