Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5C4C3L)

• DOT Name: ADP-ribosylation factor 1 (ARF1)
• Synonyms: EC 3.6.5.2
• Gene Name: ARF1
• Related Disease:
  Periventricular nodular heterotopia 8
  Periventricular nodular heterotopia
• UniProt ID: ARF1_HUMAN
• PDB ID: 1HUR; 1RE0; 1U81; 3O47; 4HMY; 6CM9; 6CRI; 6D83; 6D84; 6DFF; 6FAE; 7DN8; 7DN9; 7MGE; 7R4H; 7UX3; 8D4C; 8D4D; 8D4E; 8D4F; 8D4G; 8D9R; 8D9S; 8D9U; 8D9W; 8SDW
• EC Number: 3.6.5.2
• Pfam ID: PF00025
• Sequence:
  MGNIFANLFKGLFGKKEMRILMVGLDAAGKTTILYKLKLGEIVTTIPTIGFNVETVEYKN
  ISFTVWDVGGQDKIRPLWRHYFQNTQGLIFVVDSNDRERVNEAREELMRMLAEDELRDAV
  LLVFANKQDLPNAMNAAEITDKLGLHSLRHRNWYIQATCATSGDGLYEGLDWLSNQLRNQ
  K
• Function: Small GTPase involved in protein trafficking between different compartments. Modulates vesicle budding and uncoating within the Golgi complex. In its GTP-bound form, triggers the recruitment of coatomer proteins to the Golgi membrane. The hydrolysis of ARF1-bound GTP, which is mediated by ARFGAPs proteins, is required for dissociation of coat proteins from Golgi membranes and vesicles. The GTP-bound form interacts with PICK1 to limit PICK1-mediated inhibition of Arp2/3 complex activity; the function is linked to AMPA receptor (AMPAR) trafficking, regulation of synaptic plasticity of excitatory synapses and spine shrinkage during long-term depression (LTD). Plays a key role in the regulation of intestinal stem cells and gut microbiota, and is essential for maintaining intestinal homeostasis. Plays also a critical role in mast cell expansion but not in mast cell maturation by facilitating optimal mTORC1 activation; (Microbial infection) Functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Vibrio cholerae infection (hsa05110)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Legionellosis (hsa05134)
• Reactome Pathway:
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Nef Mediated CD4 Down-regulation (R-HSA-167590)
  trans-Golgi Network Vesicle Budding (R-HSA-199992)
  MHC class II antigen presentation (R-HSA-2132295)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Intra-Golgi traffic (R-HSA-6811438)
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Periventricular nodular heterotopia 8	DISB5A1I	Definitive	Autosomal dominant	[1]
Periventricular nodular heterotopia	DISU3ZRI	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	ADP-ribosylation factor 1 (ARF1) affects the response to substance of Temozolomide.	[18]
DTI-015	DMXZRW0	Approved	ADP-ribosylation factor 1 (ARF1) affects the response to substance of DTI-015.	[18]
Josamycin	DMKJ8LB	Approved	ADP-ribosylation factor 1 (ARF1) affects the response to substance of Josamycin.	[19]

13 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 ADP-ribosylation factor 1 (ARF1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ADP-ribosylation factor 1 (ARF1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ADP-ribosylation factor 1 (ARF1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ADP-ribosylation factor 1 (ARF1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-ribosylation factor 1 (ARF1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ADP-ribosylation factor 1 (ARF1).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of ADP-ribosylation factor 1 (ARF1).	[9]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of ADP-ribosylation factor 1 (ARF1).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of ADP-ribosylation factor 1 (ARF1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of ADP-ribosylation factor 1 (ARF1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ADP-ribosylation factor 1 (ARF1).	[15]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of ADP-ribosylation factor 1 (ARF1).	[16]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ADP-ribosylation factor 1 (ARF1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ADP-ribosylation factor 1 (ARF1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ADP-ribosylation factor 1 (ARF1).	[13]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate affects the localization of ADP-ribosylation factor 1 (ARF1).	[12]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe affects the localization of ADP-ribosylation factor 1 (ARF1).	[12]

References

• [1] Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation. NPJ Genom Med. 2016;1:16036-. doi: 10.1038/npjgenmed.2016.36. Epub 2016 Oct 5.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [11] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [12] A regulatory role for ADP-ribosylation factor 6 (ARF6) in activation of the phagocyte NADPH oxidase. J Biol Chem. 2000 Oct 20;275(42):32566-71. doi: 10.1074/jbc.M005406200.
• [13] 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.
• [14] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [17] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [18] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [19] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.