Details of Drug Off-Target (DOT)

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

• DOT Name: Myotubularin-related protein 9 (MTMR9)
• Synonyms: Inactive phosphatidylinositol 3-phosphatase 9
• Gene Name: MTMR9
• Related Disease:
  High blood pressure
  Obesity
  Prediabetes syndrome
• UniProt ID: MTMR9_HUMAN
• Pfam ID: PF06602 ; PF21098
• Sequence:
  MEFAELIKTPRVDNVVLHRPFYPAVEGTLCLTGHHLILSSRQDNTEELWLLHSNIDAIDK
  RFVGSLGTIIIKCKDFRIIQLDIPGMEECLNIASSIEALSTLDSITLMYPFFYRPMFEVI
  EDGWHSFLPEQEFELYSSATSEWRLSYVNKEFAVCPSYPPIVTVPKSIDDEALRKVATFR
  HGGRFPVLSYYHKKNGMVIMRSGQPLTGTNGRRCKEDEKLINATLRAGKRGYIIDTRSLN
  VAQQTRAKGGGFEQEAHYPQWRRIHKSIERYHILQESLIKLVEACNDQTHNMDRWLSKLE
  ASNWLTHIKEILTTACLAAQCIDREGASILIHGTEGTDSTLQVTSLAQIILEPRSRTIRG
  FEALIEREWLQAGHPFQQRCAQSAYCNTKQKWEAPVFLLFLDCVWQILRQFPCSFEFNEN
  FLIMLFEHAYASQFGTFLGNNESERCKLKLQQKTMSLWSWVNQPSELSKFTNPLFEANNL
  VIWPSVAPQSLPLWEGIFLRWNRSSKYLDEAYEEMVNIIEYNKELQAKVNILRRQLAELE
  TEDGMQESP
• Function: Acts as an adapter for myotubularin-related phosphatases. Increases lipid phosphatase MTMR6 catalytic activity, specifically towards phosphatidylinositol 3,5-bisphosphate and MTMR6 binding affinity for phosphorylated phosphatidylinositols. Positively regulates lipid phosphatase MTMR7 catalytic activity. Increases MTMR8 catalytic activity towards phosphatidylinositol 3-phosphate. The formation of the MTMR6-MTMR9 complex, stabilizes both MTMR6 and MTMR9 protein levels. Stabilizes MTMR8 protein levels. Plays a role in the late stages of macropinocytosis possibly by regulating MTMR6-mediated dephosphorylation of phosphatidylinositol 3-phosphate in membrane ruffles. Negatively regulates autophagy, in part via its association with MTMR8. Negatively regulates DNA damage-induced apoptosis, in part via its association with MTMR6. Does not bind mono-, di- and tri-phosphorylated phosphatidylinositols, phosphatidic acid and phosphatidylserine.
• Tissue Specificity: Expressed in many tissues.
• Reactome Pathway:
  Synthesis of PIPs at the late endosome membrane (R-HSA-1660517)
  Synthesis of IP2, IP, and Ins in the cytosol (R-HSA-1855183)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Strong	Genetic Variation	[1]
Obesity	DIS47Y1K	Strong	Genetic Variation	[2]
Prediabetes syndrome	DISH2I53	Strong	Genetic Variation	[2]

10 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 9 (MTMR9).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myotubularin-related protein 9 (MTMR9).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myotubularin-related protein 9 (MTMR9).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Myotubularin-related protein 9 (MTMR9).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myotubularin-related protein 9 (MTMR9).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Myotubularin-related protein 9 (MTMR9).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Myotubularin-related protein 9 (MTMR9).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Myotubularin-related protein 9 (MTMR9).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Myotubularin-related protein 9 (MTMR9).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Myotubularin-related protein 9 (MTMR9).	[13]

3 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 9 (MTMR9).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Myotubularin-related protein 9 (MTMR9).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Myotubularin-related protein 9 (MTMR9).	[9]

References

• [1] Association of single-nucleotide polymorphisms in MTMR9 gene with obesity.Hum Mol Genet. 2007 Dec 15;16(24):3017-26. doi: 10.1093/hmg/ddm260. Epub 2007 Sep 12.
• [2] The MTMR9 rs2293855 polymorphism is associated with glucose tolerance, insulin secretion, insulin sensitivity and increased risk of prediabetes.Gene. 2014 Aug 10;546(2):150-5. doi: 10.1016/j.gene.2014.06.028. Epub 2014 Jun 14.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.