Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW6I9RV)

• DOT Name: Myotubularin-related protein 5 (SBF1)
• Synonyms: Inactive phosphatidylinositol 3-phosphatase 5; SET-binding factor 1; Sbf1
• Gene Name: SBF1
• Related Disease:
  Autism spectrum disorder
  Azoospermia
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 4B3
  Colorectal carcinoma
  Head-neck squamous cell carcinoma
  Hypothyroidism
  Large granular lymphocytic leukemia
  Myocardial infarction
  Polyneuropathy
  Liposarcoma
  Melanoma
  Hereditary glaucoma
  Peripheral neuropathy
• UniProt ID: MTMR5_HUMAN
• Pfam ID: PF02141 ; PF02893 ; PF06602 ; PF00169 ; PF12335 ; PF03456
• Sequence:
  MARLADYFVLVAFGPHPRGSGEGQGQILQRFPEKDWEDNPFPQGIELFCQPSGWQLCPER
  NPPTFFVAVLTDINSERHYCACLTFWEPAEPSQQETTRVEDATEREEEGDEGGQTHLSPT
  APAPSAQLFAPKTLVLVSRLDHTEVFRNSLGLIYAIHVEGLNVCLENVIGNLLTCTVPLA
  GGSQRTISLGAGDRQVIQTPLADSLPVSRCSVALLFRQLGITNVLSLFCAALTEHKVLFL
  SRSYQRLADACRGLLALLFPLRYSFTYVPILPAQLLEVLSTPTPFIIGVNAAFQAETQEL
  LDVIVADLDGGTVTIPECVHIPPLPEPLQSQTHSVLSMVLDPELELADLAFPPPTTSTSS
  LKMQDKELRAVFLRLFAQLLQGYRWCLHVVRIHPEPVIRFHKAAFLGQRGLVEDDFLMKV
  LEGMAFAGFVSERGVPYRPTDLFDELVAHEVARMRADENHPQRVLRHVQELAEQLYKNEN
  PYPAVAMHKVQRPGESSHLRRVPRPFPRLDEGTVQWIVDQAAAKMQGAPPAVKAERRTTV
  PSGPPMTAILERCSGLHVNSARRLEVVRNCISYVFEGKMLEAKKLLPAVLRALKGRAARR
  CLAQELHLHVQQNRAVLDHQQFDFVVRMMNCCLQDCTSLDEHGIAAALLPLVTAFCRKLS
  PGVTQFAYSCVQEHVVWSTPQFWEAMFYGDVQTHIRALYLEPTEDLAPAQEVGEAPSQED
  ERSALDVASEQRRLWPTLSREKQQELVQKEESTVFSQAIHYANRMSYLLLPLDSSKSRLL
  RERAGLGDLESASNSLVTNSMAGSVAESYDTESGFEDAETCDVAGAVVRFINRFVDKVCT
  ESGVTSDHLKGLHVMVPDIVQMHIETLEAVQRESRRLPPIQKPKLLRPRLLPGEECVLDG
  LRVYLLPDGREEGAGGSAGGPALLPAEGAVFLTTYRVIFTGMPTDPLVGEQVVVRSFPVA
  ALTKEKRISVQTPVDQLLQDGLQLRSCTFQLLKMAFDEEVGSDSAELFRKQLHKLRYPPD
  IRATFAFTLGSAHTPGRPPRVTKDKGPSLRTLSRNLVKNAKKTIGRQHVTRKKYNPPSWE
  HRGQPPPEDQEDEISVSEELEPSTLTPSSALKPSDRMTMSSLVERACCRDYQRLGLGTLS
  SSLSRAKSEPFRISPVNRMYAICRSYPGLLIVPQSVQDNALQRVSRCYRQNRFPVVCWRS
  GRSKAVLLRSGGLHGKGVVGLFKAQNAPSPGQSQADSSSLEQEKYLQAVVSSMPRYADAS
  GRNTLSGFSSAHMGSHGKWGSVRTSGRSSGLGTDVGSRLAGRDALAPPQANGGPPDPGFL
  RPQRAALYILGDKAQLKGVRSDPLQQWELVPIEVFEARQVKASFKKLLKACVPGCPAAEP
  SPASFLRSLEDSEWLIQIHKLLQVSVLVVELLDSGSSVLVGLEDGWDITTQVVSLVQLLS
  DPFYRTLEGFRLLVEKEWLSFGHRFSHRGAHTLAGQSSGFTPVFLQFLDCVHQVHLQFPM
  EFEFSQFYLKFLGYHHVSRRFRTFLLDSDYERIELGLLYEEKGERRGQVPCRSVWEYVDR
  LSKRTPVFHNYMYAPEDAEVLRPYSNVSNLKVWDFYTEETLAEGPPYDWELAQGPPEPPE
  EERSDGGAPQSRRRVVWPCYDSCPRAQPDAISRLLEELQRLETELGQPAERWKDTWDRVK
  AAQRLEGRPDGRGTPSSLLVSTAPHHRRSLGVYLQEGPVGSTLSLSLDSDQSSGSTTSGS
  RQAARRSTSTLYSQFQTAESENRSYEGTLYKKGAFMKPWKARWFVLDKTKHQLRYYDHRV
  DTECKGVIDLAEVEAVAPGTPTMGAPKTVDEKAFFDVKTTRRVYNFCAQDVPSAQQWVDR
  IQSCLSDA
• Function: Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location. May function as a guanine nucleotide exchange factor (GEF) activating RAB28. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. Inhibits myoblast differentiation in vitro and induces oncogenic transformation in fibroblasts.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Synthesis of PIPs at the ER membrane (R-HSA-1483248)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[1]
Azoospermia	DIS94181	Strong	Biomarker	[2]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[3]
Charcot-Marie-Tooth disease type 4B3	DISQAYDD	Strong	Autosomal recessive	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[5]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[6]
Large granular lymphocytic leukemia	DISHOPPI	Strong	Biomarker	[7]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[8]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[3]
Liposarcoma	DIS8IZVM	moderate	Biomarker	[9]
Melanoma	DIS1RRCY	moderate	Biomarker	[10]
Hereditary glaucoma	DISJYSR1	Disputed	Genetic Variation	[11]
Peripheral neuropathy	DIS7KN5G	Disputed	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myotubularin-related protein 5 (SBF1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Myotubularin-related protein 5 (SBF1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myotubularin-related protein 5 (SBF1).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Myotubularin-related protein 5 (SBF1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Myotubularin-related protein 5 (SBF1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Myotubularin-related protein 5 (SBF1).	[15]

References

• [1] Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations. Hum Mutat. 2019 Jun;40(6):801-815. doi: 10.1002/humu.23724. Epub 2019 Apr 29.
• [2] Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1. J Clin Invest. 2002 May;109(9):1165-72. doi: 10.1172/JCI12589.
• [3] Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.Clin Genet. 2018 Nov;94(5):473-479. doi: 10.1111/cge.13419. Epub 2018 Aug 9.
• [4] Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer.Cell Death Dis. 2019 Aug 13;10(8):618. doi: 10.1038/s41419-019-1832-6.
• [5] DNA microarray reveals ZNF195 and SBF1 are potential biomarkers for gemcitabine sensitivity in head and neck squamous cell carcinoma cell lines.Int J Clin Exp Pathol. 2014 Mar 15;7(4):1514-23. eCollection 2014.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] Submicroscopic genomic rearrangements change gene expression in T-cell large granular lymphocyte leukemia.Eur J Haematol. 2014 Aug;93(2):143-9. doi: 10.1111/ejh.12318. Epub 2014 Apr 9.
• [8] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [9] SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells.J Pharmacol Sci. 2018 Dec;138(4):271-278. doi: 10.1016/j.jphs.2018.10.009. Epub 2018 Oct 24.
• [10] SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3.Biochem Pharmacol. 2012 Jul 15;84(2):172-81. doi: 10.1016/j.bcp.2012.04.006. Epub 2012 Apr 13.
• [11] Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53. doi: 10.1086/375034. Epub 2003 Apr 8.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] 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.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.