Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQWZL6R)

• DOT Name: Charged multivesicular body protein 5 (CHMP5)
• Synonyms: Chromatin-modifying protein 5; SNF7 domain-containing protein 2; Vacuolar protein sorting-associated protein 60; Vps60; hVps60
• Gene Name: CHMP5
• Related Disease:
  Acute leukaemia
  Acute myelogenous leukaemia
  Colitis
  Colon cancer
  Colon carcinoma
  leukaemia
  Leukemia
  Ulcerative colitis
  Tetralogy of fallot
• UniProt ID: CHMP5_HUMAN
• PDB ID: 2LXM; 3ULY; 3UM0; 3UM1; 3UM2; 4TXR
• Pfam ID: PF03357
• Sequence:
  MNRLFGKAKPKAPPPSLTDCIGTVDSRAESIDKKISRLDAELVKYKDQIKKMREGPAKNM
  VKQKALRVLKQKRMYEQQRDNLAQQSFNMEQANYTIQSLKDTKTTVDAMKLGVKEMKKAY
  KQVKIDQIEDLQDQLEDMMEDANEIQEALSRSYGTPELDEDDLEAELDALGDELLADEDS
  SYLDEAASAPAIPEGVPTDTKNKDGVLVDEFGLPQIPAS
• Function: Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in HIV-1 p6- and p9-dependent virus release.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)
• Reactome Pathway:
  Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729)
  Budding and maturation of HIV virion (R-HSA-162588)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Colitis	DISAF7DD	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Altered Expression	[1]
Leukemia	DISNAKFL	Strong	Altered Expression	[1]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[3]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[4]

10 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 Charged multivesicular body protein 5 (CHMP5).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Charged multivesicular body protein 5 (CHMP5).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Charged multivesicular body protein 5 (CHMP5).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Charged multivesicular body protein 5 (CHMP5).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Charged multivesicular body protein 5 (CHMP5).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Charged multivesicular body protein 5 (CHMP5).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Charged multivesicular body protein 5 (CHMP5).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Charged multivesicular body protein 5 (CHMP5).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Charged multivesicular body protein 5 (CHMP5).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Charged multivesicular body protein 5 (CHMP5).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Charged multivesicular body protein 5 (CHMP5).	[12]

References

• [1] PNAS-2: a novel gene probably participating in leukemogenesis.Oncology. 2006;71(5-6):423-9. doi: 10.1159/000108576. Epub 2007 Sep 14.
• [2] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [3] MicroRNA 429 regulates the expression of CHMP5 in the inflammatory colitis and colorectal cancer cells.Inflamm Res. 2018 Dec;67(11-12):985-996. doi: 10.1007/s00011-018-1194-z. Epub 2018 Oct 17.
• [4] The Impact of the Right Ventricular Outflow Tract Patch on Right Ventricular Strain in Tetralogy of Fallot: A Comparison with Valvar Pulmonary Stenosis Utilizing Cardiac Magnetic Resonance.Pediatr Cardiol. 2017 Mar;38(3):617-623. doi: 10.1007/s00246-016-1558-5. Epub 2017 Jan 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] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] 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.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.