Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDCLLT0)

• DOT Name: Ras-related protein Rab-39B (RAB39B)
• Gene Name: RAB39B
• Related Disease:
  Early-onset parkinsonism-intellectual disability syndrome
  Intellectual disability, X-linked 1
  Intellectual disability, X-linked 72
  Autism
  Autism spectrum disorder
  DiGeorge syndrome
  Epilepsy
  Herpes simplex infection
  Juvenile-onset Parkinson disease
  Neurodegeneration with brain iron accumulation
  Parkinsonian disorder
  Pervasive developmental disorder
  X-linked intellectual disability
  Young-onset Parkinson disease
  Influenza
  Megalencephaly
  Non-syndromic X-linked intellectual disability
  Intellectual disability
  Lewy body dementia
  Malaria
• UniProt ID: RB39B_HUMAN
• PDB ID: 6S5F
• Pfam ID: PF00071
• Sequence:
  MEAIWLYQFRLIVIGDSTVGKSCLIRRFTEGRFAQVSDPTVGVDFFSRLVEIEPGKRIKL
  QIWDTAGQERFRSITRAYYRNSVGGLLLFDITNRRSFQNVHEWLEETKVHVQPYQIVFVL
  VGHKCDLDTQRQVTRHEAEKLAAAYGMKYIETSARDAINVEKAFTDLTRDIYELVKRGEI
  TIQEGWEGVKSGFVPNVVHSSEEVVKSERRCLC
• Function: Small GTPases Rab involved in autophagy. 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 sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. May regulate the homeostasis of SNCA/alpha-synuclein. Together with PICK1 proposed to ensure selectively GRIA2 exit from the endoplasmic reticulum to the Golgi and to regulate AMPAR compostion at the post-synapses and thus synaptic transmission.
• Tissue Specificity: Highly expressed in the brain.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• 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

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Early-onset parkinsonism-intellectual disability syndrome	DIS206QS	Definitive	X-linked	[1]
Intellectual disability, X-linked 1	DISET38E	Definitive	GermlineCausalMutation	[2]
Intellectual disability, X-linked 72	DISQC206	Definitive	X-linked	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[5]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Genetic Variation	[6]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Genetic Variation	[7]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[8]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[3]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[2]
Young-onset Parkinson disease	DIS05LFS	Strong	Genetic Variation	[9]
Influenza	DIS3PNU3	moderate	Biomarker	[10]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[2]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[11]
Lewy body dementia	DISAE66J	Limited	Genetic Variation	[12]
Malaria	DISQ9Y50	Limited	Biomarker	[13]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras-related protein Rab-39B (RAB39B).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ras-related protein Rab-39B (RAB39B).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rab-39B (RAB39B).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related protein Rab-39B (RAB39B).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ras-related protein Rab-39B (RAB39B).	[17]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Ras-related protein Rab-39B (RAB39B).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related protein Rab-39B (RAB39B).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Ras-related protein Rab-39B (RAB39B).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rab-39B (RAB39B).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Ras-related protein Rab-39B (RAB39B).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras-related protein Rab-39B (RAB39B).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras-related protein Rab-39B (RAB39B).	[25]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Ras-related protein Rab-39B (RAB39B).	[26]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet. 2010 Feb 12;86(2):185-95. doi: 10.1016/j.ajhg.2010.01.011.
• [3] The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.Nat Commun. 2015 Mar 18;6:6504. doi: 10.1038/ncomms7504.
• [4] Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature.Mov Disord. 2017 Nov;32(11):1504-1523. doi: 10.1002/mds.27193.
• [5] Leucine-rich repeat-containing G protein-coupled receptor 4 facilitates vesicular stomatitis virus infection by binding vesicular stomatitis virus glycoprotein.J Biol Chem. 2017 Oct 6;292(40):16527-16538. doi: 10.1074/jbc.M117.802090. Epub 2017 Aug 23.
• [6] A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification.Mov Disord. 2016 Dec;31(12):1905-1909. doi: 10.1002/mds.26828.
• [7] High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism.Neurobiol Aging. 2015 May;36(5):2004.e9-2004.e15. doi: 10.1016/j.neurobiolaging.2015.01.020. Epub 2015 Jan 30.
• [8] Lack of RAB39B mutations in early-onset and familial Parkinson's disease in a Taiwanese cohort.Neurobiol Aging. 2017 Feb;50:169.e3-169.e4. doi: 10.1016/j.neurobiolaging.2016.10.021. Epub 2016 Oct 21.
• [9] Generation of RAB39B knockout isogenic human embryonic stem cell lines to model RAB39B-mediated Parkinson's disease.Stem Cell Res. 2018 Apr;28:161-164. doi: 10.1016/j.scr.2018.02.015. Epub 2018 Feb 21.
• [10] A Novel Sulfonated Derivative of -Cyclodextrin Effectively Inhibits Influenza A Virus Infection in vitro and in vivo.Acta Naturae. 2019 Jul-Sep;11(3):20-30. doi: 10.32607/20758251-2019-11-3-20-30.
• [11] Rabs, Membrane Dynamics, and Parkinson's Disease.J Cell Physiol. 2017 Jul;232(7):1626-1633. doi: 10.1002/jcp.25713. Epub 2016 Dec 20.
• [12] RAB39B gene mutations are not a common cause of Parkinson's disease or dementia with Lewy bodies.Neurobiol Aging. 2016 Sep;45:107-108. doi: 10.1016/j.neurobiolaging.2016.03.021. Epub 2016 Mar 24.
• [13] Predominant cell-mediated immunity in the oral mucosa: gene gun-based vaccination against infectious diseases.J Dermatol Sci. 2003 May;31(3):203-10. doi: 10.1016/s0923-1811(03)00027-6.
• [14] 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.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [21] 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.
• [22] 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.
• [23] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] 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.