Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM84KTU)

• DOT Name: Ras-related protein Rab-12 (RAB12)
• Gene Name: RAB12
• Related Disease:
  Dystonia
  Myocardial ischemia
  Gastric cancer
  Stomach cancer
• UniProt ID: RAB12_HUMAN
• PDB ID: 2IL1
• Pfam ID: PF00071
• Sequence:
  MDPGAALQRRAGGGGGLGAGSPALSGGQGRRRKQPPRPADFKLQVIIIGSRGVGKTSLME
  RFTDDTFCEACKSTVGVDFKIKTVELRGKKIRLQIWDTAGQERFNSITSAYYRSAKGIIL
  VYDITKKETFDDLPKWMKMIDKYASEDAELLLVGNKLDCETDREITRQQGEKFAQQITGM
  RFCEASAKDNFNVDEIFLKLVDDILKKMPLDILRNELSNSILSLQPEPEIPPELPPPRPH
  VRCC
• Function: The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab may play a role in protein transport from recycling endosomes to lysosomes regulating, for instance, the degradation of the transferrin receptor. Involved in autophagy.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  RAB geranylgeranylation (R-HSA-8873719)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dystonia	DISJLFGW	Strong	Biomarker	[1]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[3]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[3]

5 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-12 (RAB12).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-12 (RAB12).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ras-related protein Rab-12 (RAB12).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras-related protein Rab-12 (RAB12).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rab-12 (RAB12).	[9]

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 affects the methylation of Ras-related protein Rab-12 (RAB12).	[8]

References

• [1] Functional Characterization of Rare RAB12 Variants and Their Role in Musician's and Other Dystonias.Genes (Basel). 2017 Oct 18;8(10):276. doi: 10.3390/genes8100276.
• [2] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [3] MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression.Cancer Lett. 2017 Dec 1;410:212-227. doi: 10.1016/j.canlet.2017.09.035. Epub 2017 Sep 28.
• [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] 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.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] 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.
• [9] 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.