Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCKL3W3)

• DOT Name: Unconventional myosin-Vb (MYO5B)
• Gene Name: MYO5B
• Related Disease:
  Inborn error of metabolism
  Intestinal disorder
  Microvillus inclusion disease
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Cholestasis
  Cholestasis, progressive familial intrahepatic, 10
  Colorectal carcinoma
  Cytomegalovirus infection
  Gastric cancer
  Intrahepatic cholestasis
  Liver cancer
  Malabsorption syndrome
  Neoplasm
  Paraganglioma
  Schizophrenia
  Secretory diarrhea
  Stomach cancer
  Trichohepatoenteric syndrome
  Usher syndrome
  Progressive familial intrahepatic cholestasis type 1
  Fabry disease
  Kennedy disease
  Myopia
  Nasopharyngeal carcinoma
  Progressive familial intrahepatic cholestasis
• UniProt ID: MYO5B_HUMAN
• PDB ID: 4J5M; 4LNZ; 4LWZ; 4LX0
• Pfam ID: PF01843 ; PF00612 ; PF00063
• Sequence:
  MSVGELYSQCTRVWIPDPDEVWRSAELTKDYKEGDKSLQLRLEDETILEYPIDVQRNQLP
  FLRNPDILVGENDLTALSYLHEPAVLHNLKVRFLESNHIYTYCGIVLVAINPYEQLPIYG
  QDVIYTYSGQNMGDMDPHIFAVAEEAYKQMARDEKNQSIIVSGESGAGKTVSAKYAMRYF
  ATVGGSASETNIEEKVLASSPIMEAIGNAKTTRNDNSSRFGKYIQIGFDKRYHIIGANMR
  TYLLEKSRVVFQADDERNYHIFYQLCAAAGLPEFKELALTSAEDFFYTSQGGDTSIEGVD
  DAEDFEKTRQAFTLLGVKESHQMSIFKIIASILHLGSVAIQAERDGDSCSISPQDVYLSN
  FCRLLGVEHSQMEHWLCHRKLVTTSETYVKTMSLQQVINARNALAKHIYAQLFGWIVEHI
  NKALHTSLKQHSFIGVLDIYGFETFEVNSFEQFCINYANEKLQQQFNSHVFKLEQEEYMK
  EQIPWTLIDFYDNQPCIDLIEAKLGILDLLDEECKVPKGTDQNWAQKLYDRHSSSQHFQK
  PRMSNTAFIIVHFADKVEYLSDGFLEKNRDTVYEEQINILKASKFPLVADLFHDDKDPVP
  ATTPGKGSSSKISVRSARPPMKVSNKEHKKTVGHQFRTSLHLLMETLNATTPHYVRCIKP
  NDEKLPFHFDPKRAVQQLRACGVLETIRISAAGYPSRWAYHDFFNRYRVLVKKRELANTD
  KKAICRSVLENLIKDPDKFQFGRTKIFFRAGQVAYLEKLRADKFRTATIMIQKTVRGWLQ
  KVKYHRLKGATLTLQRYCRGHLARRLAEHLRRIRAAVVLQKHYRMQRARQAYQRVRRAAV
  VIQAFTRAMFVRRTYRQVLMEHKATTIQKHVRGWMARRHFQRLRDAAIVIQCAFRMLKAR
  RELKALRIEARSAEHLKRLNVGMENKVVQLQRKIDEQNKEFKTLSEQLSVTTSTYTMEVE
  RLKKELVHYQQSPGEDTSLRLQEEVESLRTELQRAHSERKILEDAHSREKDELRKRVADL
  EQENALLKDEKEQLNNQILCQSKDEFAQNSVKENLMKKELEEERSRYQNLVKEYSQLEQR
  YDNLRDEMTIIKQTPGHRRNPSNQSSLESDSNYPSISTSEIGDTEDALQQVEEIGLEKAA
  MDMTVFLKLQKRVRELEQERKKLQVQLEKREQQDSKKVQAEPPQTDIDLDPNADLAYNSL
  KRQELESENKKLKNDLNELRKAVADQATQNNSSHGSPDSYSLLLNQLKLAHEELEVRKEE
  VLILRTQIVSADQRRLAGRNAEPNINARSSWPNSEKHVDQEDAIEAYHGVCQTNSKTEDW
  GYLNEDGELGLAYQGLKQVARLLEAQLQAQSLEHEEEVEHLKAQLEALKEEMDKQQQTFC
  QTLLLSPEAQVEFGVQQEISRLTNENLDLKELVEKLEKNERKLKKQLKIYMKKAQDLEAA
  QALAQSERKRHELNRQVTVQRKEKDFQGMLEYHKEDEALLIRNLVTDLKPQMLSGTVPCL
  PAYILYMCIRHADYTNDDLKVHSLLTSTINGIKKVLKKHNDDFEMTSFWLSNTCRLLHCL
  KQYSGDEGFMTQNTAKQNEHCLKNFDLTEYRQVLSDLSIQIYQQLIKIAEGVLQPMIVSA
  MLENESIQGLSGVKPTGYRKRSSSMADGDNSYCLEAIIRQMNAFHTVMCDQGLDPEIILQ
  VFKQLFYMINAVTLNNLLLRKDVCSWSTGMQLRYNISQLEEWLRGRNLHQSGAVQTMEPL
  IQAAQLLQLKKKTQEDAEAICSLCTSLSTQQIVKILNLYTPLNEFEERVTVAFIRTIQAQ
  LQERNDPQQLLLDAKHMFPVLFPFNPSSLTMDSIHIPACLNLEFLNEV
• Function: May be involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. Required in a complex with RAB11A and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. Together with RAB11A participates in CFTR trafficking to the plasma membrane and TF (transferrin) recycling in nonpolarized cells. Together with RAB11A and RAB8A participates in epithelial cell polarization. Together with RAB25 regulates transcytosis. Required for proper localization of bile salt export pump ABCB11 at the apical/canalicular plasma membrane of hepatocytes.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway: Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inborn error of metabolism	DISO5FAY	Definitive	Biomarker	[1]
Intestinal disorder	DISGPMUQ	Definitive	Biomarker	[1]
Microvillus inclusion disease	DIS6L4RW	Definitive	Autosomal recessive	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Cholestasis	DISDJJWE	Strong	Genetic Variation	[4]
Cholestasis, progressive familial intrahepatic, 10	DISTF4Z6	Strong	Autosomal recessive	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Cytomegalovirus infection	DISCEMGC	Strong	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Intrahepatic cholestasis	DISHITDZ	Strong	Genetic Variation	[7]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Malabsorption syndrome	DISGMUVS	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Secretory diarrhea	DISBX8WG	Strong	Genetic Variation	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[13]
Usher syndrome	DIS9YIS7	Strong	Genetic Variation	[14]
Progressive familial intrahepatic cholestasis type 1	DISU0AJE	Supportive	Autosomal recessive	[4]
Fabry disease	DISUUQJF	Limited	Altered Expression	[15]
Kennedy disease	DISXZVM1	Limited	Genetic Variation	[16]
Myopia	DISK5S60	Limited	Genetic Variation	[17]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[18]
Progressive familial intrahepatic cholestasis	DIS3J8HT	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Unconventional myosin-Vb (MYO5B) affects the response to substance of Methamphetamine.	[35]

3 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 Unconventional myosin-Vb (MYO5B).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Unconventional myosin-Vb (MYO5B).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Unconventional myosin-Vb (MYO5B).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Unconventional myosin-Vb (MYO5B).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Unconventional myosin-Vb (MYO5B).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Unconventional myosin-Vb (MYO5B).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Unconventional myosin-Vb (MYO5B).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Unconventional myosin-Vb (MYO5B).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Unconventional myosin-Vb (MYO5B).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Unconventional myosin-Vb (MYO5B).	[26]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Unconventional myosin-Vb (MYO5B).	[26]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Unconventional myosin-Vb (MYO5B).	[27]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Unconventional myosin-Vb (MYO5B).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Unconventional myosin-Vb (MYO5B).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Unconventional myosin-Vb (MYO5B).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Unconventional myosin-Vb (MYO5B).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Unconventional myosin-Vb (MYO5B).	[34]

References

• [1] MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008 Oct;40(10):1163-5. doi: 10.1038/ng.225. Epub 2008 Aug 24.
• [2] Bipolar disorder risk alleles in adult ADHD patients.Genes Brain Behav. 2011 Jun;10(4):418-23. doi: 10.1111/j.1601-183X.2011.00680.x. Epub 2011 Feb 18.
• [3] Myosin Vb gene is associated with schizophrenia in Chinese Han population.Psychiatry Res. 2013 May 15;207(1-2):13-8. doi: 10.1016/j.psychres.2013.02.026. Epub 2013 Apr 3.
• [4] MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology. 2017 Jan;65(1):164-173. doi: 10.1002/hep.28779. Epub 2016 Oct 5.
• [5] Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence.Br J Cancer. 2017 Nov 21;117(11):1689-1701. doi: 10.1038/bjc.2017.352. Epub 2017 Oct 12.
• [6] Inactivation of MYO5B promotes invasion and motility in gastric cancer cells.Dig Dis Sci. 2012 May;57(5):1247-52. doi: 10.1007/s10620-011-1989-z. Epub 2011 Dec 2.
• [7] A Molecular Mechanism Underlying Genotype-Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations.Hepatology. 2020 Jul;72(1):213-229. doi: 10.1002/hep.31002. Epub 2020 Apr 23.
• [8] Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.PLoS One. 2014 Jul 24;9(7):e102579. doi: 10.1371/journal.pone.0102579. eCollection 2014.
• [9] Myosin Vb and Rab11a regulate phosphorylation of ezrin in enterocytes.J Cell Sci. 2014 Mar 1;127(Pt 5):1007-17. doi: 10.1242/jcs.137273. Epub 2014 Jan 10.
• [10] Loss of MYO5B expression deregulates late endosome size which hinders mitotic spindle orientation.PLoS Biol. 2019 Nov 4;17(11):e3000531. doi: 10.1371/journal.pbio.3000531. eCollection 2019 Nov.
• [11] Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes.Int J Cancer. 2016 May 1;138(9):2201-11. doi: 10.1002/ijc.29957. Epub 2015 Dec 30.
• [12] Glucocorticoids and myosin5b loss of function induce heightened PKA signaling in addition to membrane traffic defects.Mol Biol Cell. 2019 Dec 15;30(26):3076-3089. doi: 10.1091/mbc.E18-07-0415. Epub 2019 Oct 30.
• [13] The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease.Biol Cell. 2016 Jan;108(1):19-28. doi: 10.1111/boc.201500034. Epub 2015 Dec 8.
• [14] An overview and online registry of microvillus inclusion disease patients and their MYO5B mutations.Hum Mutat. 2013 Dec;34(12):1597-605. doi: 10.1002/humu.22440. Epub 2013 Oct 16.
• [15] Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease.J Hum Genet. 2016 Feb;61(2):143-9. doi: 10.1038/jhg.2015.123. Epub 2015 Oct 22.
• [16] Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease.J Clin Invest. 2014 Jul;124(7):2947-62. doi: 10.1172/JCI71651. Epub 2014 Jun 2.
• [17] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [18] Knockdown Rab11-FIP2 inhibits migration and invasion of nasopharyngeal carcinoma via suppressing Rho GTPase signaling.J Cell Biochem. 2020 Feb;121(2):1072-1086. doi: 10.1002/jcb.29344. Epub 2019 Aug 26.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [23] 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.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [26] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [27] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [28] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [29] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [34] 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.
• [35] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.