Details of Drug Off-Target (DOT)

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

• DOT Name: Myotubularin-related protein 2 (MTMR2)
• Synonyms: Phosphatidylinositol-3,5-bisphosphate 3-phosphatase; EC 3.1.3.95; Phosphatidylinositol-3-phosphate phosphatase; EC 3.1.3.64
• Gene Name: MTMR2
• Related Disease:
  Charcot-Marie-Tooth disease type 1B
  Demyelinating hereditary motor and sensory neuropathy
  X-linked myotubular myopathy
  Centronuclear myopathy
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 4
  Charcot-Marie-Tooth disease type 4B1
  Charcot-Marie-Tooth disease type 4B2
  Congenital structural myopathy
  Demyelinating polyneuropathy
  Hereditary motor and sensory neuropathy
  Myopathy
  Peripheral neuropathy
  Peripheral sensory neuropathies
  Hereditary glaucoma
  Charcot-Marie-Tooth disease type 3
  Gastric cancer
  Glaucoma/ocular hypertension
  Metastatic malignant neoplasm
  Neoplasm
  Stomach cancer
• UniProt ID: MTMR2_HUMAN
• PDB ID: 1LW3; 1M7R; 1ZSQ; 1ZVR; 5GNH
• EC Number: 3.1.3.64; 3.1.3.95
• Pfam ID: PF02893 ; PF06602
• Sequence:
  MEKSSSCESLGSQPAAARPPSVDSLSSASTSHSENSVHTKSASVVSSDSISTSADNFSPD
  LRVLRESNKLAEMEEPPLLPGENIKDMAKDVTYICPFTGAVRGTLTVTNYRLYFKSMERD
  PPFVLDASLGVINRVEKIGGASSRGENSYGLETVCKDIRNLRFAHKPEGRTRRSIFENLM
  KYAFPVSNNLPLFAFEYKEVFPENGWKLYDPLLEYRRQGIPNESWRITKINERYELCDTY
  PALLVVPANIPDEELKRVASFRSRGRIPVLSWIHPESQATITRCSQPMVGVSGKRSKEDE
  KYLQAIMDSNAQSHKIFIFDARPSVNAVANKAKGGGYESEDAYQNAELVFLDIHNIHVMR
  ESLRKLKEIVYPNIEETHWLSNLESTHWLEHIKLILAGALRIADKVESGKTSVVVHCSDG
  WDRTAQLTSLAMLMLDGYYRTIRGFEVLVEKEWLSFGHRFQLRVGHGDKNHADADRSPVF
  LQFIDCVWQMTRQFPTAFEFNEYFLITILDHLYSCLFGTFLCNSEQQRGKENLPKRTVSL
  WSYINSQLEDFTNPLYGSYSNHVLYPVASMRHLELWVGYYIRWNPRMKPQEPIHNRYKEL
  LAKRAELQKKVEELQREISNRSTSSSERASSPAQCVTPVQTVV
• Function: Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Binds phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Stabilizes SBF2/MTMR13 at the membranes. Specifically in peripheral nerves, stabilizes SBF2/MTMR13 protein.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
  Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)
  Synthesis of PIPs at the late endosome membrane (R-HSA-1660517)
  Synthesis of PIPs at the ER membrane (R-HSA-1483248)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease type 1B	DISJRS1V	Definitive	Biomarker	[1]
Demyelinating hereditary motor and sensory neuropathy	DISZTO2L	Definitive	Autosomal recessive	[2]
X-linked myotubular myopathy	DISJ95GS	Definitive	Altered Expression	[3]
Centronuclear myopathy	DISXBEJO	Strong	Genetic Variation	[4]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 4	DISM8IZN	Strong	Genetic Variation	[6]
Charcot-Marie-Tooth disease type 4B1	DISSXR87	Strong	Autosomal recessive	[7]
Charcot-Marie-Tooth disease type 4B2	DIS7PXQ7	Strong	Biomarker	[8]
Congenital structural myopathy	DISZ9JP4	Strong	Genetic Variation	[4]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Genetic Variation	[8]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Biomarker	[9]
Myopathy	DISOWG27	Strong	Altered Expression	[10]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[10]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[11]
Hereditary glaucoma	DISJYSR1	Disputed	Genetic Variation	[12]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[9]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[13]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[14]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[15]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Myotubularin-related protein 2 (MTMR2) decreases the response to substance of Camptothecin.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Myotubularin-related protein 2 (MTMR2).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Myotubularin-related protein 2 (MTMR2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Myotubularin-related protein 2 (MTMR2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myotubularin-related protein 2 (MTMR2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myotubularin-related protein 2 (MTMR2).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Myotubularin-related protein 2 (MTMR2).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Myotubularin-related protein 2 (MTMR2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Myotubularin-related protein 2 (MTMR2).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Myotubularin-related protein 2 (MTMR2).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Myotubularin-related protein 2 (MTMR2).	[24]

References

• [1] Sural nerve biopsy and functional studies support the pathogenic role of a novel MPZ mutation.Neuropathology. 2015 Jun;35(3):254-9. doi: 10.1111/neup.12179. Epub 2014 Nov 11.
• [2] 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.
• [3] Intravenous Administration of a MTMR2-Encoding AAV Vector Ameliorates the Phenotype of Myotubular Myopathy in Mice.J Neuropathol Exp Neurol. 2018 Apr 1;77(4):282-295. doi: 10.1093/jnen/nly002.
• [4] Amphiphysin 2 modulation rescues myotubular myopathy and prevents focal adhesion defects in mice.Sci Transl Med. 2019 Mar 20;11(484):eaav1866. doi: 10.1126/scitranslmed.aav1866.
• [5] A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).Ann Neurol. 2019 Jul;86(1):55-67. doi: 10.1002/ana.25500. Epub 2019 May 27.
• [6] SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology. 2013 Jul 9;81(2):165-73. doi: 10.1212/WNL.0b013e31829a3421. Epub 2013 Jun 7.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination.ASN Neuro. 2018 Jan-Dec;10:1759091418803282. doi: 10.1177/1759091418803282.
• [9] An animal model for Charcot-Marie-Tooth disease type 4B1.Hum Mol Genet. 2005 Dec 1;14(23):3685-95. doi: 10.1093/hmg/ddi400. Epub 2005 Oct 25.
• [10] Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy.Hum Mol Genet. 2017 Oct 1;26(19):3736-3748. doi: 10.1093/hmg/ddx258.
• [11] Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.Neuromuscul Disord. 2011 Aug;21(8):543-50. doi: 10.1016/j.nmd.2011.04.013. Epub 2011 Jul 7.
• [12] 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.
• [13] MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFN/STAT1 signaling.J Exp Clin Cancer Res. 2019 May 21;38(1):206. doi: 10.1186/s13046-019-1186-z.
• [14] SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma.Neurology. 2004 Aug 10;63(3):577-80. doi: 10.1212/01.wnl.0000133211.40288.9a.
• [15] PTEN: its deregulation and tumorigenesis.Biol Pharm Bull. 2007 Sep;30(9):1624-7. doi: 10.1248/bpb.30.1624.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] 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.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] 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.
• [20] 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.
• [21] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [22] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.