Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQPAWI3)

• DOT Name: Myotubularin-related protein 6 (MTMR6)
• Synonyms: Phosphatidylinositol-3,5-bisphosphate 3-phosphatase; EC 3.1.3.95; Phosphatidylinositol-3-phosphate phosphatase; EC 3.1.3.64
• Gene Name: MTMR6
• Related Disease: Advanced cancer
• UniProt ID: MTMR6_HUMAN
• PDB ID: 2YF0
• EC Number: 3.1.3.64; 3.1.3.95
• Pfam ID: PF06602 ; PF21098
• Sequence:
  MEHIRTTKVEQVKLLDRFSTSNKSLTGTLYLTATHLLFIDSHQKETWILHHHIASVEKLA
  LTTSGCPLVIQCKNFRTVHFIVPRERDCHDIYNSLLQLSKQAKYEDLYAFSYNPKQNDSE
  RLQGWQLIDLAEEYKRMGVPNSHWQLSDANRDYKICETYPRELYVPRIASKPIIVGSSKF
  RSKGRFPVLSYYHQDKEAAICRCSQPLSGFSARCLEDEHLLQAISKANPVNRYMYVMDTR
  PKLNAMANRAAGKGYENEDNYSNIRFQFVGIENIHVMRSSLQKLLEVNGTKGLSVNDFYS
  GLESSGWLRHIKAVMDAAIFLAKAITVENASVLVHCSDGWDRTSQVCSLGSLLLDSYYRT
  IKGFMVLIEKDWISFGHKFSERCGQLDGDPKEVSPVFTQFLECVWHLTEQFPQAFEFSEA
  FLLQIHEHIHSCQFGNFLGNCQKEREELKLKEKTYSLWPFLLEDQKKYLNPLYSSESHRF
  TVLEPNTVSFNFKFWRNMYHQFDRTLHPRQSVFNIIMNMNEQNKQLEKDIKDLESKIKQR
  KNKQTDGILTKELLHSVHPESPNLKTSLCFKEQTLLPVNDALRTIEGSSPADNRYSEYAE
  EFSKSEPAVVSLEYGVARMTC
• Function: Phosphatase that acts on lipids with a phosphoinositol headgroup. Dephosphorylates phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,5-bisphosphate (Probable). Binds with high affinity to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) but also to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P), phosphatidic acid and phosphatidylserine. Negatively regulates ER-Golgi protein transport. Probably in association with MTMR9, plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3-phosphate in membrane ruffles. Acts as a negative regulator of KCNN4/KCa3.1 channel activity in CD4(+) T-cells possibly by decreasing intracellular levels of phosphatidylinositol 3-phosphate. Negatively regulates proliferation of reactivated CD4(+) T-cells. In complex with MTMR9, negatively regulates DNA damage-induced apoptosis. The formation of the MTMR6-MTMR9 complex stabilizes both MTMR6 and MTMR9 protein levels.
• Tissue Specificity: Expressed in CD4+ T-cells.
• 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)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Myotubularin-related protein 6 (MTMR6).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Myotubularin-related protein 6 (MTMR6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Myotubularin-related protein 6 (MTMR6).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myotubularin-related protein 6 (MTMR6).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Myotubularin-related protein 6 (MTMR6).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Myotubularin-related protein 6 (MTMR6).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Myotubularin-related protein 6 (MTMR6).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Myotubularin-related protein 6 (MTMR6).	[10]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Myotubularin-related protein 6 (MTMR6).	[4]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Myotubularin-related protein 6 (MTMR6).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Myotubularin-related protein 6 (MTMR6).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Myotubularin-related protein 6 (MTMR6).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Myotubularin-related protein 6 (MTMR6).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myotubularin-related protein 6 (MTMR6).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Myotubularin-related protein 6 (MTMR6).	[6]

References

• [1] The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays.Blood. 2003 Jun 1;101(11):4598-606. doi: 10.1182/blood-2002-06-1743. Epub 2003 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-186.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.