Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT18H5HD)

• DOT Name: Guanine nucleotide exchange factor for Rab-3A (RAB3IL1)
• Synonyms: Rab-3A-interacting-like protein 1; Rab3A-interacting-like protein 1; Rabin3-like 1
• Gene Name: RAB3IL1
• Related Disease:
  Bacteremia
  Streptococcal toxic-shock syndrome
• UniProt ID: R3GEF_HUMAN
• PDB ID: 4LI0
• Pfam ID: PF06428
• Sequence:
  MWSGPPQPDQGLPPPLAAVPVPWKSTDPCQGHRESPGALVETSAGEEAQGQEGPAAAQLD
  VLRLRSSSMEIREKGSEFLKEELHRAQKELKLKDEECERLSKVREQLEQELEELTASLFE
  EAHKMVREANMKQAASEKQLKEARGKIDMLQAEVTALKTLVITSTPASPNRELHPQLLSP
  TKAGPRKGHSRHKSTSSTLCPAVCPAAGHTLTPDREGKEVDTILFAEFQAWRESPTLDKT
  CPFLERVYREDVGPCLDFTMQELSVLVRAAVEDNTLTIEPVASQTLPTVKVAEVDCSSTN
  TCALSGLTRTCRHRIRLGDSKSHYYISPSSRARITAVCNFFTYIRYIQQGLVRQDAEPMF
  WEIMRLRKEMSLAKLGFFPQEA
• Function: Guanine nucleotide exchange factor (GEF) which may activate RAB3A, a GTPase that regulates synaptic vesicle exocytosis. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. May also activate RAB8A and RAB8B.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Altered Expression	[1]
Streptococcal toxic-shock syndrome	DISCVXCW	Definitive	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Guanine nucleotide exchange factor for Rab-3A (RAB3IL1) affects the response to substance of NAPQI.	[15]

2 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 Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[2]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Guanine nucleotide exchange factor for Rab-3A (RAB3IL1).	[13]

References

• [1] Low antibody levels against cell wall-attached proteins of Streptococcus pyogenes predispose for severe invasive disease.J Infect Dis. 2004 Mar 1;189(5):797-804. doi: 10.1086/381982. Epub 2004 Feb 18.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [14] 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.
• [15] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.