Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAZWZH7)

• DOT Name: Autophagy-related protein 9A (ATG9A)
• Synonyms: APG9-like 1; mATG9
• Gene Name: ATG9A
• Related Disease:
  Carcinoma
  Epithelial ovarian cancer
  Ovarian cancer
  Advanced cancer
  Benign prostatic hyperplasia
  Colitis
  Cryptococcosis
  Inflammatory bowel disease
  Neuroaxonal dystrophy
  Triple negative breast cancer
  Ulcerative colitis
  Adult glioblastoma
  Glioblastoma multiforme
  Female hypogonadism
  Neoplasm
• UniProt ID: ATG9A_HUMAN
• PDB ID: 6WQZ; 6WR4; 7JLO; 7JLP; 7JLQ
• Pfam ID: PF04109
• Sequence:
  MAQFDTEYQRLEASYSDSPPGEEDLLVHVAEGSKSPWHHIENLDLFFSRVYNLHQKNGFT
  CMLIGEIFELMQFLFVVAFTTFLVSCVDYDILFANKMVNHSLHPTEPVKVTLPDAFLPAQ
  VCSARIQENGSLITILVIAGVFWIHRLIKFIYNICCYWEIHSFYLHALRIPMSALPYCTW
  QEVQARIVQTQKEHQICIHKRELTELDIYHRILRFQNYMVALVNKSLLPLRFRLPGLGEA
  VFFTRGLKYNFELILFWGPGSLFLNEWSLKAEYKRGGQRLELAQRLSNRILWIGIANFLL
  CPLILIWQILYAFFSYAEVLKREPGALGARCWSLYGRCYLRHFNELEHELQSRLNRGYKP
  ASKYMNCFLSPLLTLLAKNGAFFAGSILAVLIALTIYDEDVLAVEHVLTTVTLLGVTVTV
  CRSFIPDQHMVFCPEQLLRVILAHIHYMPDHWQGNAHRSQTRDEFAQLFQYKAVFILEEL
  LSPIVTPLILIFCLRPRALEIIDFFRNFTVEVVGVGDTCSFAQMDVRQHGHPQWLSAGQT
  EASVYQQAEDGKTELSLMHFAITNPGWQPPRESTAFLGFLKEQVQRDGAAASLAQGGLLP
  ENALFTSIQSLQSESEPLSLIANVVAGSSCRGPPLPRDLQGSRHRAEVASALRSFSPLQP
  GQAPTGRAHSTMTGSGVDARTASSGSSVWEGQLQSLVLSEYASTEMSLHALYMHQLHKQQ
  AQAEPERHVWHRRESDESGESAPDEGGEGARAPQSIPRSASYPCAAPRPGAPETTALHGG
  FQRRYGGITDPGTVPRVPSHFSRLPLGGWAEDGQSASRHPEPVPEEGSEDELPPQVHKV
• Function: Phospholipid scramblase involved in autophagy by mediating autophagosomal membrane expansion. Cycles between the preautophagosomal structure/phagophore assembly site (PAS) and the cytoplasmic vesicle pool and supplies membrane for the growing autophagosome. Lipid scramblase activity plays a key role in preautophagosomal structure/phagophore assembly by distributing the phospholipids that arrive through ATG2 (ATG2A or ATG2B) from the cytoplasmic to the luminal leaflet of the bilayer, thereby driving autophagosomal membrane expansion. Also required to supply phosphatidylinositol 4-phosphate to the autophagosome initiation site by recruiting the phosphatidylinositol 4-kinase beta (PI4KB) in a process dependent on ARFIP2, but not ARFIP1. In addition to autophagy, also plays a role in necrotic cell death.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Altered Expression	[1]
Ovarian cancer	DISZJHAP	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[3]
Colitis	DISAF7DD	Strong	Altered Expression	[4]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[6]
Neuroaxonal dystrophy	DISHSV8Z	Strong	Biomarker	[7]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[8]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[9]
Female hypogonadism	DISWASB4	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Autophagy-related protein 9A (ATG9A).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Autophagy-related protein 9A (ATG9A).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Autophagy-related protein 9A (ATG9A).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Autophagy-related protein 9A (ATG9A).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Autophagy-related protein 9A (ATG9A).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Autophagy-related protein 9A (ATG9A).	[15]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Autophagy-related protein 9A (ATG9A).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Autophagy-related protein 9A (ATG9A).	[17]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Autophagy-related protein 9A (ATG9A).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Autophagy-related protein 9A (ATG9A).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Autophagy-related protein 9A (ATG9A).	[21]

References

• [1] Involvement of miR-29b signaling in the sensitivity to chemotherapy in patients with ovarian carcinoma.Hum Pathol. 2014 Jun;45(6):1285-93. doi: 10.1016/j.humpath.2014.02.008. Epub 2014 Feb 28.
• [2] Mammalian autophagy and the plasma membrane.FEBS J. 2017 Mar;284(5):672-679. doi: 10.1111/febs.13931. Epub 2016 Nov 6.
• [3] Deregulation of ATG9A by impaired AR signaling induces autophagy in prostate stromal fibroblasts and promotes BPH progression.Cell Death Dis. 2018 Apr 1;9(4):431. doi: 10.1038/s41419-018-0415-2.
• [4] MiR-29a inhibited intestinal epithelial cells autophagy partly by decreasing ATG9A in ulcerative colitis.Anticancer Drugs. 2018 Aug;29(7):652-659. doi: 10.1097/CAD.0000000000000636.
• [5] Functional analysis of host factors that mediate the intracellular lifestyle of Cryptococcus neoformans.PLoS Pathog. 2011 Jun;7(6):e1002078. doi: 10.1371/journal.ppat.1002078. Epub 2011 Jun 16.
• [6] Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease.Genome Biol. 2016 Nov 30;17(1):247. doi: 10.1186/s13059-016-1100-3.
• [7] Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome.PLoS Genet. 2018 Apr 26;14(4):e1007363. doi: 10.1371/journal.pgen.1007363. eCollection 2018 Apr.
• [8] ATG9A Is Overexpressed in Triple Negative Breast Cancer and Its In Vitro Extinction Leads to the Inhibition of Pro-Cancer Phenotypes.Cells. 2018 Dec 6;7(12):248. doi: 10.3390/cells7120248.
• [9] Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A.Br J Cancer. 2017 Sep 5;117(6):813-825. doi: 10.1038/bjc.2017.263. Epub 2017 Aug 10.
• [10] ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure.Genet Med. 2019 Apr;21(4):930-938. doi: 10.1038/s41436-018-0287-y. Epub 2018 Sep 19.
• [11] TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A.Cell Death Dis. 2017 Aug 31;8(8):e3031. doi: 10.1038/cddis.2017.370.
• [12] 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.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] 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.
• [15] 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.
• [16] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [19] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [20] 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.
• [21] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.