Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3KHIE)

• DOT Name: ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1)
• Synonyms: ARF GAP 1; ADP-ribosylation factor 1 GTPase-activating protein; ARF1 GAP; ARF1-directed GTPase-activating protein
• Gene Name: ARFGAP1
• Related Disease:
  Colorectal carcinoma
  Neoplasm
  Nervous system disease
  Parkinson disease
• UniProt ID: ARFG1_HUMAN
• PDB ID: 3DWD; 3O47
• Pfam ID: PF01412
• Sequence:
  MASPRTRKVLKEVRVQDENNVCFECGAFNPQWVSVTYGIWICLECSGRHRGLGVHLSFVR
  SVTMDKWKDIELEKMKAGGNAKFREFLESQEDYDPCWSLQEKYNSRAAALFRDKVVALAE
  GREWSLESSPAQNWTPPQPRTLPSMVHRVSGQPQSVTASSDKAFEDWLNDDLGSYQGAQG
  NRYVGFGNTPPPQKKEDDFLNNAMSSLYSGWSSFTTGASRFASAAKEGATKFGSQASQKA
  SELGHSLNENVLKPAQEKVKEGKIFDDVSSGVSQLASKVQGVGSKGWRDVTTFFSGKAEG
  PLDSPSEGHSYQNSGLDHFQNSNIDQSFWETFGSAEPTKTRKSPSSDSWTCADTSTERRS
  SDSWEVWGSASTNRNSNSDGGEGGEGTKKAVPPAVPTDDGWDNQNW
• Function: GTPase-activating protein (GAP) for the ADP ribosylation factor 1 (ARF1). Involved in membrane trafficking and /or vesicle transport. Promotes hydrolysis of the ARF1-bound GTP and thus, is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles, a prerequisite for vesicle's fusion with target compartment. Probably regulates ARF1-mediated transport via its interaction with the KDELR proteins and TMED2. Overexpression induces the redistribution of the entire Golgi complex to the endoplasmic reticulum, as when ARF1 is deactivated. Its activity is stimulated by phosphoinosides and inhibited by phosphatidylcholine.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[2]
Parkinson disease	DISQVHKL	Limited	Biomarker	[3]

4 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 ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP-ribosylation factor GTPase-activating protein 1 (ARFGAP1).	[11]

References

• [1] Involvement of small ArfGAP1 (SMAP1), a novel Arf6-specific GTPase-activating protein, in microsatellite instability oncogenesis.Oncogene. 2014 May 22;33(21):2758-67. doi: 10.1038/onc.2013.211. Epub 2013 Jun 10.
• [2] A genotype-first approach for the molecular and clinical characterization of uncommon de novo microdeletion of 20q13.33.PLoS One. 2010 Aug 27;5(8):e12462. doi: 10.1371/journal.pone.0012462.
• [3] GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1.PLoS Genet. 2012;8(2):e1002526. doi: 10.1371/journal.pgen.1002526. Epub 2012 Feb 9.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Identification of novel genes associated with the response to 5-FU treatment in gastric cancer cell lines using a cDNA microarray. Cancer Lett. 2004 Oct 8;214(1):19-33.
• [10] 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.
• [11] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.