Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTR4H7S)

• DOT Name: Ras-related protein Rab-32 (RAB32)
• Gene Name: RAB32
• Related Disease:
  Allergic contact dermatitis
  Leprosy
  Colitis
  Encephalitis
  Hepatitis C virus infection
  Hermansky-Pudlak syndrome
  HIV infectious disease
  Inflammatory bowel disease
  Multiple sclerosis
  Nervous system inflammation
  Parkinson disease
  Adenocarcinoma
  Endometrial carcinoma
  Gastric cancer
  Marinesco-Sjogren syndrome
  Neoplasm
  Stomach cancer
  Colon cancer
• UniProt ID: RAB32_HUMAN
• PDB ID: 4CYM; 4CZ2; 5OEC; 5OED; 6FF8
• Pfam ID: PF00071
• Sequence:
  MAGGGAGDPGLGAAAAPAPETREHLFKVLVIGELGVGKTSIIKRYVHQLFSQHYRATIGV
  DFALKVLNWDSRTLVRLQLWDIAGQERFGNMTRVYYKEAVGAFVVFDISRSSTFEAVLKW
  KSDLDSKVHLPNGSPIPAVLLANKCDQNKDSSQSPSQVDQFCKEHGFAGWFETSAKDNIN
  IEEAARFLVEKILVNHQSFPNEENDVDKIKLDQETLRAENKSQCC
• Function: Acts as an A-kinase anchoring protein by binding to the type II regulatory subunit of protein kinase A and anchoring it to the mitochondrion. Also involved in synchronization of mitochondrial fission. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays an important role in the control of melanin production and melanosome biogenesis. In concert with RAB38, regulates the proper trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to melanosomes in melanocytes.
• Tissue Specificity: Widely expressed with high levels in heart, liver, kidney, bone marrow, testis, colon and fetal lung.
• 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

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic contact dermatitis	DISFFVF9	Definitive	Biomarker	[1]
Leprosy	DISAA4UI	Definitive	Genetic Variation	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Encephalitis	DISLD1RL	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[5]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[4]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[4]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[8]
Adenocarcinoma	DIS3IHTY	moderate	Posttranslational Modification	[9]
Endometrial carcinoma	DISXR5CY	moderate	Posttranslational Modification	[9]
Gastric cancer	DISXGOUK	moderate	Posttranslational Modification	[9]
Marinesco-Sjogren syndrome	DISKEU0B	moderate	Genetic Variation	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[9]
Stomach cancer	DISKIJSX	moderate	Posttranslational Modification	[9]
Colon cancer	DISVC52G	Limited	Biomarker	[9]

16 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-32 (RAB32).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-related protein Rab-32 (RAB32).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rab-32 (RAB32).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rab-32 (RAB32).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-32 (RAB32).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related protein Rab-32 (RAB32).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-related protein Rab-32 (RAB32).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Ras-related protein Rab-32 (RAB32).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-32 (RAB32).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras-related protein Rab-32 (RAB32).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ras-related protein Rab-32 (RAB32).	[20]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Ras-related protein Rab-32 (RAB32).	[1]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rab-32 (RAB32).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Ras-related protein Rab-32 (RAB32).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-32 (RAB32).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras-related protein Rab-32 (RAB32).	[26]

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 increases the methylation of Ras-related protein Rab-32 (RAB32).	[22]

References

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• [2] A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs.Genet Epidemiol. 2014 Sep;38(6):560-71. doi: 10.1002/gepi.21842. Epub 2014 Jul 8.
• [3] Rab32-related antimicrobial pathway is involved in the progression of dextran sodium sulfate-induced colitis.FEBS Open Bio. 2018 Sep 21;8(10):1658-1668. doi: 10.1002/2211-5463.12514. eCollection 2018 Oct.
• [4] Rab32 connects ER stress to mitochondrial defects in multiple sclerosis.J Neuroinflammation. 2017 Jan 23;14(1):19. doi: 10.1186/s12974-016-0788-z.
• [5] Hepatitis C Virus-Induced Rab32 Aggregation and Its Implications for Virion Assembly.J Virol. 2017 Jan 18;91(3):e01662-16. doi: 10.1128/JVI.01662-16. Print 2017 Feb 1.
• [6] The BLOC-3 subunit HPS4 is required for activation of Rab32/38 GTPases in melanogenesis, but its Rab9 activity is dispensable for melanogenesis.J Biol Chem. 2019 Apr 26;294(17):6912-6922. doi: 10.1074/jbc.RA119.007345. Epub 2019 Mar 5.
• [7] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [8] Rab32 interacts with SNX6 and affects retromer-dependent Golgi trafficking.PLoS One. 2019 Jan 14;14(1):e0208889. doi: 10.1371/journal.pone.0208889. eCollection 2019.
• [9] RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas.Int J Cancer. 2006 Aug 15;119(4):801-6. doi: 10.1002/ijc.21912.
• [10] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [11] 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.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [18] 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.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [22] 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.
• [23] 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.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.