Details of Drug Off-Target (DOT)

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

• DOT Name: Cysteine protease ATG4A (ATG4A)
• Synonyms: EC 3.4.22.-; AUT-like 2 cysteine endopeptidase; Autophagy-related cysteine endopeptidase 2; Autophagin-2; Autophagy-related protein 4 homolog A; HsAPG4A; hAPG4A
• Gene Name: ATG4A
• Related Disease:
  Crohn disease
  Glioma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Metastatic malignant neoplasm
  Stomach cancer
  Lung cancer
  Lung carcinoma
• UniProt ID: ATG4A_HUMAN
• PDB ID: 2P82
• EC Number: 3.4.22.-
• Pfam ID: PF20166 ; PF03416
• Sequence:
  MESVLSKYEDQITIFTDYLEEYPDTDELVWILGKQHLLKTEKSKLLSDISARLWFTYRRK
  FSPIGGTGPSSDAGWGCMLRCGQMMLAQALICRHLGRDWSWEKQKEQPKEYQRILQCFLD
  RKDCCYSIHQMAQMGVGEGKSIGEWFGPNTVAQVLKKLALFDEWNSLAVYVSMDNTVVIE
  DIKKMCRVLPLSADTAGDRPPDSLTASNQSKGTSAYCSAWKPLLLIVPLRLGINQINPVY
  VDAFKECFKMPQSLGALGGKPNNAYYFIGFLGDELIFLDPHTTQTFVDTEENGTVNDQTF
  HCLQSPQRMNILNLDPSVALGFFCKEEKDFDNWCSLVQKEILKENLRMFELVQKHPSHWP
  PFVPPAKPEVTTTGAEFIDSTEQLEEFDLEEDFEILSV
• Function: Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins to reveal a C-terminal glycine. Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy. Preferred substrate is GABARAPL2 followed by MAP1LC3A and GABARAP. Protease activity is also required to counteract formation of high-molecular weight conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8 conjugated to other proteins, such as ATG3. In addition to the protease activity, also mediates delipidation of ATG8 family proteins. Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. Compared to ATG4B, the major protein for proteolytic activation of ATG8 proteins, shows weaker ability to cleave the C-terminal amino acid of ATG8 proteins, while it displays stronger delipidation activity. Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Biomarker	[3]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[3]
Gastric cancer	DISXGOUK	moderate	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[4]
Stomach cancer	DISKIJSX	moderate	Biomarker	[4]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[5]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[5]

10 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 Cysteine protease ATG4A (ATG4A).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cysteine protease ATG4A (ATG4A).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cysteine protease ATG4A (ATG4A).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cysteine protease ATG4A (ATG4A).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cysteine protease ATG4A (ATG4A).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cysteine protease ATG4A (ATG4A).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Cysteine protease ATG4A (ATG4A).	[12]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin increases the expression of Cysteine protease ATG4A (ATG4A).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cysteine protease ATG4A (ATG4A).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cysteine protease ATG4A (ATG4A).	[16]

1 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 increases the methylation of Cysteine protease ATG4A (ATG4A).	[15]

References

• [1] Granulomas in Crohn's disease: are newly discovered genetic variants involved?.J Crohns Colitis. 2010 Oct;4(4):438-43. doi: 10.1016/j.crohns.2010.02.006. Epub 2010 Apr 22.
• [2] -catenin regulates effects of miR-24 on the viability and autophagy of glioma cells.Exp Ther Med. 2019 Aug;18(2):1285-1290. doi: 10.3892/etm.2019.7680. Epub 2019 Jun 18.
• [3] A mammosphere formation RNAi screen reveals that ATG4A promotes a breast cancer stem-like phenotype.Breast Cancer Res. 2013 Nov 14;15(6):R109. doi: 10.1186/bcr3576.
• [4] ATG4A promotes tumor metastasis by inducing the epithelial-mesenchymal transition and stem-like properties in gastric cells.Oncotarget. 2016 Jun 28;7(26):39279-39292. doi: 10.18632/oncotarget.9827.
• [5] An intron SNP rs807185 in ATG4A decreases the risk of lung cancer in a southwest Chinese population.Eur J Cancer Prev. 2016 Jul;25(4):255-8. doi: 10.1097/CEJ.0000000000000174.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.