Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3B517W)

• DOT Name: Myotubularin (MTM1)
• Synonyms: Phosphatidylinositol-3,5-bisphosphate 3-phosphatase; EC 3.1.3.95; Phosphatidylinositol-3-phosphate phosphatase; EC 3.1.3.64
• Gene Name: MTM1
• Related Disease: X-linked myotubular myopathy
• UniProt ID: MTM1_HUMAN
• EC Number: 3.1.3.64; 3.1.3.95
• Pfam ID: PF02893 ; PF06602
• Sequence:
  MASASTSKYNSHSLENESIKRTSRDGVNRDLTEAVPRLPGETLITDKEVIYICPFNGPIK
  GRVYITNYRLYLRSLETDSSLILDVPLGVISRIEKMGGATSRGENSYGLDITCKDMRNLR
  FALKQEGHSRRDMFEILTRYAFPLAHSLPLFAFLNEEKFNVDGWTVYNPVEEYRRQGLPN
  HHWRITFINKCYELCDTYPALLVVPYRASDDDLRRVATFRSRNRIPVLSWIHPENKTVIV
  RCSQPLVGMSGKRNKDDEKYLDVIRETNKQISKLTIYDARPSVNAVANKATGGGYESDDA
  YHNAELFFLDIHNIHVMRESLKKVKDIVYPNVEESHWLSSLESTHWLEHIKLVLTGAIQV
  ADKVSSGKSSVLVHCSDGWDRTAQLTSLAMLMLDSFYRSIEGFEILVQKEWISFGHKFAS
  RIGHGDKNHTDADRSPIFLQFIDCVWQMSKQFPTAFEFNEQFLIIILDHLYSCRFGTFLF
  NCESARERQKVTERTVSLWSLINSNKEKFKNPFYTKEINRVLYPVASMRHLELWVNYYIR
  WNPRIKQQQPNPVEQRYMELLALRDEYIKRLEELQLANSAKLSDPPTSPSSPSQMMPHVQ
  THF
• Function: Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Has also been shown to dephosphorylate phosphotyrosine- and phosphoserine-containing peptides. Negatively regulates EGFR degradation through regulation of EGFR trafficking from the late endosome to the lysosome. Plays a role in vacuolar formation and morphology. Regulates desmin intermediate filament assembly and architecture. Plays a role in mitochondrial morphology and positioning. Required for skeletal muscle maintenance but not for myogenesis. In skeletal muscles, stabilizes MTMR12 protein levels.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  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 plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked myotubular myopathy	DISJ95GS	Definitive	X-linked	[1]

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 Myotubularin (MTM1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Myotubularin (MTM1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Myotubularin (MTM1).	[8]

7 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 Myotubularin (MTM1).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Myotubularin (MTM1).	[4]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Myotubularin (MTM1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Myotubularin (MTM1).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Myotubularin (MTM1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Myotubularin (MTM1).	[10]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Myotubularin (MTM1).	[11]

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] 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.
• [3] 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.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.