Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY1KEHY)

• DOT Name: Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1)
• Synonyms: BFA-resistant GEF 1
• Gene Name: GBF1
• Related Disease:
  Alzheimer disease
  Axonal neuropathy
  Enterovirus infection
  Hepatitis C virus infection
  Parkinson disease
  Hepatitis E virus infection
• UniProt ID: GBF1_HUMAN
• Pfam ID: PF01369 ; PF12783
• Sequence:
  MVDKNIYIIQGEINIVVGAIKRNARWSTHTPLDEERDPLLHSFGHLKEVLNSITELSEIE
  PNVFLRPFLEVIRSEDTTGPITGLALTSVNKFLSYALIDPTHEGTAEGMENMADAVTHAR
  FVGTDPASDEVVLMKILQVLRTLLLTPVGAHLTNESVCEIMQSCFRICFEMRLSELLRKS
  AEHTLVDMVQLLFTRLPQFKEEPKNYVGTNMKKLKMRAGGMSDSSKWKKQKRSPRPPRHM
  TKVTPGSELPTPNGTTLSSNLTGGMPFIDVPTPISSASSEAASAVVSPSTDSGLEFSSQT
  TSKEDLTDLEQPGSPGYSTATEPGSSELGVPEQPDLQQEGTHVEKSQSASVESIPEVLEE
  CTSPADHSDSASVHDMDYVNPRGVRFTQSSQKEGTALVPYGLPCIRELFRFLISLTNPHD
  RHNSEVMIHMGLHLLTVALESAPVAQCQTLLGLIKDEMCRHLFQLLSIERLNLYAASLRV
  CFLLFESMREHLKFQMEMYIKKLMEIITVENPKMPYEMKEMALEAIVQLWRIPSFVTELY
  INYDCDYYCSNLFEELTKLLSKNAFPVSGQLYTTHLLSLDALLTVIDSTEAHCQAKVLNS
  LTQQEKKETARPSCEIVDGTREASNTERTASDGKAVGMASDIPGLHLPGGGRLPPEHGKS
  GCSDLEEAVDSGADKKFARKPPRFSCLLPDPRELIEIKNKKKLLITGTEQFNQKPKKGIQ
  FLQEKGLLTIPMDNTEVAQWLRENPRLDKKMIGEFVSDRKNIDLLESFVSTFSFQGLRLD
  EALRLYLEAFRLPGEAPVIQRLLEAFTERWMNCNGSPFANSDACFSLAYAVIMLNTDQHN
  HNVRKQNAPMTLEEFRKNLKGVNGGKDFEQDILEDMYHAIKNEEIVMPEEQTGLVRENYV
  WNVLLHRGATPEGIFLRVPTASYDLDLFTMTWGPTIAALSYVFDKSLEETIIQKAISGFR
  KCAMISAHYGLSDVFDNLIISLCKFTALSSESIENLPSVFGSNPKAHIAAKTVFHLAHRH
  GDILREGWKNIMEAMLQLFRAQLLPKAMIEVEDFVDPNGKISLQREETPSNRGESTVLSF
  VSWLTLSGPEQSSVRGPSTENQEAKRVALECIKQCDPEKMITESKFLQLESLQELMKALV
  SVTPDEETYDEEDAAFCLEMLLRIVLENRDRVGCVWQTVRDHLYHLCVQAQDFCFLVERA
  VVGLLRLAIRLLRREEISAQVLLSLRILLLMKPSVLSRVSHQVAYGLHELLKTNAANIHS
  GDDWATLFTLLECIGSGVKPPAALQATARADAPDAGAQSDSELPSYHQNDVSLDRGYTSD
  SEVYTDHGRPGKIHRSATDADVVNSGWLVVGKDDVDNSKPGPSRPGPSPLINQYSLTVGL
  DLGPHDTKSLLKCVESLSFIVRDAAHITPDNFELCVKTLRIFVEASLNGGCKSQEKRGKS
  HKYDSKGNRFKKKSKEGSMLRRPRTSSQHASRGGQSDDDEDEGVPASYHTVSLQVSQDLL
  DLMHTLHTRAASIYSSWAEEQRHLETGGQKIEADSRTLWAHCWCPLLQGIACLCCDARRQ
  VRMQALTYLQRALLVHDLQKLDALEWESCFNKVLFPLLTKLLENISPADVGGMEETRMRA
  STLLSKVFLQHLSPLLSLSTFAALWLTILDFMDKYMHAGSSDLLSEAIPESLKNMLLVMD
  TAEIFHSADARGGGPSALWEITWERIDCFLPHLRDELFKQTVIQDPMPMEPQGQKPLASA
  HLTSAAGDTRTPGHPPPPEIPSELGACDFEKPESPRAASSSSPGSPVASSPSRLSPTPDG
  PPPLAQPPLILQPLASPLQVGVPPMTLPIILNPALIEATSPVPLLATPRPTDPIPTSEVN
• Function: Guanine-nucleotide exchange factor (GEF) for members of the Arf family of small GTPases involved in trafficking in the early secretory pathway; its GEF activity initiates the coating of nascent vesicles via the localized generation of activated ARFs through replacement of GDP with GTP. Recruitment to cis-Golgi membranes requires membrane association of Arf-GDP and can be regulated by ARF1, ARF3, ARF4 and ARF5. Involved in the recruitment of the COPI coat complex to the endoplasmic reticulum exit sites (ERES), and the endoplasmic reticulum-Golgi intermediate (ERGIC) and cis-Golgi compartments which implicates ARF1 activation. Involved in COPI vesicle-dependent retrograde transport from the ERGIC and cis-Golgi compartments to the endoplasmic reticulum (ER). Involved in the trans-Golgi network recruitment of GGA1, GGA2, GGA3, BIG1, BIG2, and the AP-1 adaptor protein complex related to chlathrin-dependent transport; the function requires its GEF activity (probably at least in part on ARF4 and ARF5). Has GEF activity towards ARF1. Has in vitro GEF activity towards ARF5. Involved in the processing of PSAP. Required for the assembly of the Golgi apparatus. The AMPK-phosphorylated form is involved in Golgi disassembly during mitotis and under stress conditions. May be involved in the COPI vesicle-dependent recruitment of PNPLA2 to lipid droplets; however, this function is under debate. In neutrophils, involved in G protein-coupled receptor (GPCR)-mediated chemotaxis und superoxide production. Proposed to be recruited by phosphatidylinositol-phosphates generated upon GPCR stimulation to the leading edge where it recruits and activates ARF1, and is involved in recruitment of GIT2 and the NADPH oxidase complex. Plays a role in maintaining mitochondrial morphology.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  VxPx cargo-targeting to cilium (R-HSA-5620916)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  trans-Golgi Network Vesicle Budding (R-HSA-199992)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Axonal neuropathy	DIS5S2BC	Strong	Autosomal dominant	[2]
Enterovirus infection	DISH2UDP	Strong	Biomarker	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[4]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[5]
Hepatitis E virus infection	DIS0TXIR	Disputed	Biomarker	[6]

9 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 Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[17]

3 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 affects the methylation of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1).	[15]

References

• [1] Regulatory role of Golgi brefeldin A resistance factor-1 in amyloid precursor protein trafficking, cleavage and A formation.J Cell Biochem. 2019 Sep;120(9):15604-15615. doi: 10.1002/jcb.28827. Epub 2019 May 20.
• [2] De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation. Am J Hum Genet. 2020 Oct 1;107(4):763-777. doi: 10.1016/j.ajhg.2020.08.018. Epub 2020 Sep 15.
• [3] A Redundant Mechanism of Recruitment Underlies the Remarkable Plasticity of the Requirement of Poliovirus Replication for the Cellular ArfGEF GBF1.J Virol. 2019 Oct 15;93(21):e00856-19. doi: 10.1128/JVI.00856-19. Print 2019 Nov 1.
• [4] Functional and Physical Interaction between the Arf Activator GBF1 and Hepatitis C Virus NS3 Protein.J Virol. 2019 Mar 5;93(6):e01459-18. doi: 10.1128/JVI.01459-18. Print 2019 Mar 15.
• [5] A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci.Nat Genet. 2017 Oct;49(10):1511-1516. doi: 10.1038/ng.3955. Epub 2017 Sep 11.
• [6] Identification of GBF1 as a cellular factor required for hepatitis E virus RNA replication.Cell Microbiol. 2018 Jan;20(1):e12804. doi: 10.1111/cmi.12804. Epub 2017 Nov 17.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] 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.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.