Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2GIUO5)

• DOT Name: Ras-related protein Rab-3A (RAB3A)
• Gene Name: RAB3A
• Related Disease:
  Attention deficit hyperactivity disorder
  Acute leukaemia
  Alzheimer disease
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Cone-rod dystrophy 7
  Diabetic kidney disease
  Ependymoma
  Glioblastoma multiforme
  Glioma
  Insulinoma
  Neoplasm
  Nervous system neoplasm
  Fetal growth restriction
  Hepatocellular carcinoma
  Intellectual disability
• UniProt ID: RAB3A_HUMAN
• Pfam ID: PF00071
• Sequence:
  MASATDSRYGQKESSDQNFDYMFKILIIGNSSVGKTSFLFRYADDSFTPAFVSTVGIDFK
  VKTIYRNDKRIKLQIWDTAGQERYRTITTAYYRGAMGFILMYDITNEESFNAVQDWSTQI
  KTYSWDNAQVLLVGNKCDMEDERVVSSERGRQLADHLGFEFFEASAKDNINVKQTFERLV
  DVICEKMSESLDTADPAVTGAKQGPQLSDQQVPPHQDCAC
• Function: Small GTP-binding protein that plays a central role in regulated exocytosis and secretion. Controls the recruitment, tethering and docking of secretory vesicles to the plasma membrane. Upon stimulation, switches to its active GTP-bound form, cycles to vesicles and recruits effectors such as RIMS1, RIMS2, Rabphilin-3A/RPH3A, RPH3AL or SYTL4 to help the docking of vesicules onto the plasma membrane. Upon GTP hydrolysis by GTPase-activating protein, dissociates from the vesicle membrane allowing the exocytosis to proceed. Stimulates insulin secretion through interaction with RIMS2 or RPH3AL effectors in pancreatic beta cells. Regulates calcium-dependent lysosome exocytosis and plasma membrane repair (PMR) via the interaction with 2 effectors, SYTL4 and myosin-9/MYH9. Acts as a positive regulator of acrosome content secretion in sperm cells by interacting with RIMS1. Also plays a role in the regulation of dopamine release by interacting with synaptotagmin I/SYT. Interacts with MADD (via uDENN domain); the GTP-bound form is preferred for interaction.
• Tissue Specificity: Specifically expressed in brain.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Insulin secretion (hsa04911)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)
  Neutrophil degranulation (R-HSA-6798695)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Cone-rod dystrophy 7	DISVA5ZE	Strong	Genetic Variation	[6]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[7]
Ependymoma	DISUMRNZ	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Insulinoma	DISIU1JS	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Nervous system neoplasm	DIS141UP	Strong	Altered Expression	[10]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[12]
Intellectual disability	DISMBNXP	Limited	Biomarker	[13]

8 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 Ras-related protein Rab-3A (RAB3A).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras-related protein Rab-3A (RAB3A).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-3A (RAB3A).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-3A (RAB3A).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Ras-related protein Rab-3A (RAB3A).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras-related protein Rab-3A (RAB3A).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ras-related protein Rab-3A (RAB3A).	[21]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Ras-related protein Rab-3A (RAB3A).	[22]

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 decreases the methylation of Ras-related protein Rab-3A (RAB3A).	[20]

References

• [1] DNA variants in the human RAB3A gene are not associated with autism.Genes Brain Behav. 2004 Apr;3(2):123-4. doi: 10.1111/j.1601-183x.2003.00058.x.
• [2] Biparental inheritance of chromosomal abnormalities in male twins with non-syndromic mental retardation.Eur J Med Genet. 2011 Jul-Aug;54(4):e383-8. doi: 10.1016/j.ejmg.2011.03.008. Epub 2011 Mar 21.
• [3] Reduced expression of amyloid precursor protein, presenilin-1 and rab3a in cortical brain regions in Alzheimer's disease.Dement Geriatr Cogn Disord. 2001 Jul-Aug;12(4):243-50. doi: 10.1159/000051266.
• [4] Rab3a promotes brain tumor initiation and progression.Mol Biol Rep. 2014 Sep;41(9):5903-11. doi: 10.1007/s11033-014-3465-2. Epub 2014 Jun 26.
• [5] Evidence of Rab3A expression, regulation of vesicle trafficking, and cellular secretion in response to heregulin in mammary epithelial cells.Mol Cell Biol. 2000 Dec;20(23):9092-101. doi: 10.1128/MCB.20.23.9092-9101.2000.
• [6] Genomic organisation and alternative splicing of human RIM1, a gene implicated in autosomal dominant cone-rod dystrophy (CORD7). Genomics. 2003 Mar;81(3):304-14. doi: 10.1016/s0888-7543(03)00010-7.
• [7] Proteinuria and glomerular damage in Rab3A knockout mice chronically fed a high-glucose diet.Nephron Exp Nephrol. 2012;120(2):e69-80. doi: 10.1159/000336166. Epub 2012 Mar 30.
• [8] An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes.Nat Genet. 2015 Aug;47(8):878-87. doi: 10.1038/ng.3323. Epub 2015 Jun 15.
• [9] Expression of the ras-related rab3a gene in human insulinomas and normal human pancreatic islets.Pancreas. 1994 Jul;9(4):434-8. doi: 10.1097/00006676-199407000-00004.
• [10] Specific expression of the ras-related rab3A gene in human normal and malignant neuroendocrine cells.Cancer. 1992 Nov 15;70(10):2552-6. doi: 10.1002/1097-0142(19921115)70:10<2552::aid-cncr2820701026>3.0.co;2-q.
• [11] Intrauterine growth retardation leads to the functional change of insulin secretion in the newborn rats.Horm Metab Res. 2010 Jun;42(7):491-5. doi: 10.1055/s-0030-1249058. Epub 2010 Mar 11.
• [12] O-GlcNAcylation on Rab3A attenuates its effects on mitochondrial oxidative phosphorylation and metastasis in hepatocellular carcinoma.Cell Death Dis. 2018 Sep 20;9(10):970. doi: 10.1038/s41419-018-0961-7.
• [13] Variants in the RAB3A gene are not associated with mental retardation in the Chinese population.Neurosci Lett. 2006 Jun 19;401(1-2):114-8. doi: 10.1016/j.neulet.2006.02.079. Epub 2006 Apr 11.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] 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.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] 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.
• [21] 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.
• [22] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.