Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPZDKI0)

• DOT Name: Beclin 1-associated autophagy-related key regulator (ATG14)
• Synonyms: Barkor; Autophagy-related protein 14-like protein; Atg14L
• Gene Name: ATG14
• Related Disease:
  Advanced cancer
  Amyotrophic lateral sclerosis
  Bone osteosarcoma
  Colorectal carcinoma
  Fetal growth restriction
  Osteosarcoma
  Hepatitis C virus infection
  Nasopharyngeal carcinoma
• UniProt ID: BAKOR_HUMAN
• PDB ID: 6HOL; 8SOR; 8SRQ
• Pfam ID: PF10186
• Sequence:
  MASPSGKGARALEAPGCGPRPLARDLVDSVDDAEGLYVAVERCPLCNTTRRRLTCAKCVQ
  SGDFVYFDGRDRERFIDKKERLSRLKSKQEEFQKEVLKAMEGKWITDQLRWKIMSCKMRI
  EQLKQTICKGNEEMEKNSEGLLKTKEKNQKLYSRAQRHQEKKEKIQRHNRKLGDLVEKKT
  IDLRSHYERLANLRRSHILELTSVIFPIEEVKTGVRDPADVSSESDSAMTSSTVSKLAEA
  RRTTYLSGRWVCDDHNGDTSISITGPWISLPNNGDYSAYYSWVEEKKTTQGPDMEQSNPA
  YTISAALCYATQLVNILSHILDVNLPKKLCNSEFCGENLSKQKFTRAVKKLNANILYLCF
  SQHVNLDQLQPLHTLRNLMYLVSPSSEHLGRSGPFEVRADLEESMEFVDPGVAGESDESG
  DERVSDEETDLGTDWENLPSPRFCDIPSQSVEVSQSQSTQASPPIASSSAGGMISSAAAS
  VTSWFKAYTGHR
• Function: Required for both basal and inducible autophagy. Determines the localization of the autophagy-specific PI3-kinase complex PI3KC3-C1. Plays a role in autophagosome formation and MAP1LC3/LC3 conjugation to phosphatidylethanolamine. Promotes BECN1 translocation from the trans-Golgi network to autophagosomes. Enhances PIK3C3 activity in a BECN1-dependent manner. Essential for the autophagy-dependent phosphorylation of BECN1. Stimulates the phosphorylation of BECN1, but suppresses the phosphorylation PIK3C3 by AMPK. Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion. Modulates the hepatic lipid metabolism.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway:
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[4]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[5]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[3]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[13]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin increases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Beclin 1-associated autophagy-related key regulator (ATG14).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Beclin 1-associated autophagy-related key regulator (ATG14).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Beclin 1-associated autophagy-related key regulator (ATG14).	[16]

References

• [1] ATG14 facilitated lipophagy in cancer cells induce ER stress mediated mitoptosis through a ROS dependent pathway.Free Radic Biol Med. 2017 Mar;104:199-213. doi: 10.1016/j.freeradbiomed.2017.01.007. Epub 2017 Jan 6.
• [2] Neuropathy-causing mutations in HSPB1 impair autophagy by disturbing the formation of SQSTM1/p62 bodies.Autophagy. 2019 Jun;15(6):1051-1068. doi: 10.1080/15548627.2019.1569930. Epub 2019 Jan 31.
• [3] Silencing of Barkor/ATG14 sensitizes osteosarcoma cells to cisplatininduced apoptosis.Int J Mol Med. 2014 Feb;33(2):271-6. doi: 10.3892/ijmm.2013.1578. Epub 2013 Dec 9.
• [4] SNHG14 stimulates cell autophagy to facilitate cisplatin resistance of colorectal cancer by regulating miR-186/ATG14 axis.Biomed Pharmacother. 2020 Jan;121:109580. doi: 10.1016/j.biopha.2019.109580. Epub 2019 Nov 5.
• [5] Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway.J Reprod Dev. 2017 Dec 15;63(6):547-554. doi: 10.1262/jrd.2017-050. Epub 2017 Aug 31.
• [6] RACK1 mediates rewiring of intracellular networks induced by hepatitis C virus infection.PLoS Pathog. 2019 Sep 16;15(9):e1008021. doi: 10.1371/journal.ppat.1008021. eCollection 2019 Sep.
• [7] Upregulation of lncRNA HAGLROS enhances the development of nasopharyngeal carcinoma via modulating miR-100/ATG14 axis-mediated PI3K/AKT/mTOR signals.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):3043-3052. doi: 10.1080/21691401.2019.1640233.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Prenatal dexamethasone exposure caused fetal rats liver dysplasia by inhibiting autophagy-mediated cell proliferation. Toxicology. 2021 Feb 15;449:152664. doi: 10.1016/j.tox.2020.152664. Epub 2021 Jan 5.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] 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.
• [18] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.