Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ZABOU)

• DOT Name: Methylthioribulose-1-phosphate dehydratase (APIP)
• Synonyms: MTRu-1-P dehydratase; EC 4.2.1.109; APAF1-interacting protein; hAPIP
• Gene Name: APIP
• Related Disease:
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Myocardial infarction
  Neoplasm
  Non-small-cell lung cancer
  Pulmonary disease
  Gastric cancer
  Stomach cancer
  Anaplastic astrocytoma
  Breast cancer
  Breast carcinoma
  Melanoma
  Pancreatic cancer
  T-cell acute lymphoblastic leukaemia
• UniProt ID: MTNB_HUMAN
• PDB ID: 4M6R
• EC Number: 4.2.1.109
• Pfam ID: PF00596
• Sequence:
  MSGCDAREGDCCSRRCGAQDKEHPRYLIPELCKQFYHLGWVTGTGGGISLKHGDEIYIAP
  SGVQKERIQPEDMFVCDINEKDISGPSPSKKLKKSQCTPLFMNAYTMRGAGAVIHTHSKA
  AVMATLLFPGREFKITHQEMIKGIKKCTSGGYYRYDDMLVVPIIENTPEEKDLKDRMAHA
  MNEYPDSCAVLVRRHGVYVWGETWEKAKTMCECYDYLFDIAVSMKKVGLDPSQLPVGENG
  IV
• Function: Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). Functions in the methionine salvage pathway, which plays a key role in cancer, apoptosis, microbial proliferation and inflammation. May inhibit the CASP1-related inflammatory response (pyroptosis), the CASP9-dependent apoptotic pathway and the cytochrome c-dependent and APAF1-mediated cell death.
• Tissue Specificity: Isoform 1 is ubiquitously expressed. Isoform 2 is expressed at lower levels and detected in heart, brain, pancreas, liver, placenta, skeletal muscle and kidney.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Methionine salvage pathway (R-HSA-1237112)
  Regulation of the apoptosome activity (R-HSA-9627069)
  Formation of apoptosome (R-HSA-111458)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[1]
Myocardial infarction	DIS655KI	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Pulmonary disease	DIS6060I	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	moderate	Biomarker	[5]
Stomach cancer	DISKIJSX	moderate	Biomarker	[5]
Anaplastic astrocytoma	DISSBE0K	Disputed	Biomarker	[6]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[6]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[6]
Melanoma	DIS1RRCY	Disputed	Biomarker	[6]
Pancreatic cancer	DISJC981	Disputed	Biomarker	[6]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Disputed	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Methylthioribulose-1-phosphate dehydratase (APIP).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methylthioribulose-1-phosphate dehydratase (APIP).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Methylthioribulose-1-phosphate dehydratase (APIP).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Methylthioribulose-1-phosphate dehydratase (APIP).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Methylthioribulose-1-phosphate dehydratase (APIP).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Methylthioribulose-1-phosphate dehydratase (APIP).	[12]

References

• [1] Cardioprotective role of APIP in myocardial infarction through ADORA2B.Cell Death Dis. 2019 Jul 1;10(7):511. doi: 10.1038/s41419-019-1746-3.
• [2] CD44-SLC1A2 fusion transcripts in primary colorectal cancer.Pathol Oncol Res. 2015 Jul;21(3):759-64. doi: 10.1007/s12253-014-9887-2. Epub 2015 Jan 10.
• [3] APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis.Oncotarget. 2016 Apr 19;7(16):21601-17. doi: 10.18632/oncotarget.7802.
• [4] Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.Nat Commun. 2015 Sep 29;6:8382. doi: 10.1038/ncomms9382.
• [5] Molecular heterogeneity in the novel fusion gene APIP-FGFR2: Diversity of genomic breakpoints in gastric cancer with high-level amplifications at 11p13 and 10q26.Oncol Lett. 2017 Jan;13(1):215-221. doi: 10.3892/ol.2016.5386. Epub 2016 Nov 15.
• [6] Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types.PLoS Genet. 2013 Apr;9(4):e1003464. doi: 10.1371/journal.pgen.1003464. Epub 2013 Apr 25.
• [7] 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.
• [8] 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.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] 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.
• [11] 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.
• [12] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.