Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOP49DM)

• DOT Name: Methylthioribose-1-phosphate isomerase (MRI1)
• Synonyms: M1Pi; MTR-1-P isomerase; EC 5.3.1.23; Mediator of RhoA-dependent invasion; S-methyl-5-thioribose-1-phosphate isomerase; Translation initiation factor eIF-2B subunit alpha/beta/delta-like protein
• Gene Name: MRI1
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Neoplasm
  Asthma
  Metastatic malignant neoplasm
  Metastatic melanoma
• UniProt ID: MTNA_HUMAN
• PDB ID: 4LDQ; 4LDR
• EC Number: 5.3.1.23
• Pfam ID: PF01008
• Sequence:
  MTLEAIRYSRGSLQILDQLLLPKQSRYEAVGSVHQAWEAIRAMKVRGAPAIALVGCLSLA
  VELQAGAGGPGLAALVAFVRDKLSFLVTARPTAVNMARAARDLADVAAREAEREGATEEA
  VRERVICCTEDMLEKDLRDNRSIGDLGARHLLERVAPSGGKVTVLTHCNTGALATAGYGT
  ALGVIRSLHSLGRLEHAFCTETRPYNQGARLTAFELVYEQIPATLITDSMVAAAMAHRGV
  SAVVVGADRVVANGDTANKVGTYQLAIVAKHHGIPFYVAAPSSSCDLRLETGKEIIIEER
  PGQELTDVNGVRIAAPGIGVWNPAFDVTPHDLITGGIITELGVFAPEELRTALTTTISSR
  DGTLDGPQM
• Function: Catalyzes the interconversion of methylthioribose-1-phosphate (MTR-1-P) into methylthioribulose-1-phosphate (MTRu-1-P). Independently from catalytic activity, promotes cell invasion in response to constitutive RhoA activation by promoting FAK tyrosine phosphorylation and stress fiber turnover.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Methionine salvage pathway (R-HSA-1237112)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[2]
Asthma	DISW9QNS	Limited	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[2]
Metastatic melanoma	DISSL43L	Limited	Altered Expression	[4]

1 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 Methylthioribose-1-phosphate isomerase (MRI1).	[5]

11 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 Methylthioribose-1-phosphate isomerase (MRI1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methylthioribose-1-phosphate isomerase (MRI1).	[16]

References

• [1] Texture analysis of T1-w and T2-w MR images allows a quantitative evaluation of radiation-induced changes of internal obturator muscles after radiotherapy for prostate cancer.Med Phys. 2018 Apr;45(4):1518-1528. doi: 10.1002/mp.12798. Epub 2018 Feb 26.
• [2] Changes in Brain Metastasis During Radiosurgical Planning.Int J Radiat Oncol Biol Phys. 2018 Nov 15;102(4):727-733. doi: 10.1016/j.ijrobp.2018.06.021. Epub 2018 Jun 25.
• [3] Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy.Pediatr Pulmonol. 2014 Sep;49(9):852-62. doi: 10.1002/ppul.22930. Epub 2013 Oct 25.
• [4] Structure of mediator of RhoA-dependent invasion (MRDI) explains its dual function as a metabolic enzyme and a mediator of cell invasion.Biochemistry. 2013 Aug 20;52(33):5675-84. doi: 10.1021/bi400556e. Epub 2013 Jul 31.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [15] 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.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.