Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV53D33)

• DOT Name: Charged multivesicular body protein 2a (CHMP2A)
• Synonyms: Chromatin-modifying protein 2a; CHMP2a; Putative breast adenocarcinoma marker BC-2; Vacuolar protein sorting-associated protein 2-1; Vps2-1; hVps2-1
• Gene Name: CHMP2A
• Related Disease: Frontotemporal dementia
• UniProt ID: CHM2A_HUMAN
• PDB ID: 7ZCG; 7ZCH
• Pfam ID: PF03357
• Sequence:
  MDLLFGRRKTPEELLRQNQRALNRAMRELDRERQKLETQEKKIIADIKKMAKQGQMDAVR
  IMAKDLVRTRRYVRKFVLMRANIQAVSLKIQTLKSNNSMAQAMKGVTKAMGTMNRQLKLP
  QIQKIMMEFERQAEIMDMKEEMMNDAIDDAMGDEEDEEESDAVVSQVLDELGLSLTDELS
  NLPSTGGSLSVAAGGKKAEAAASALADADADLEERLKNLRRD
• Function: Probable core 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. Together with SPAST, the ESCRT-III complex promotes nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Recruited to the reforming nuclear envelope (NE) during anaphase by LEMD2. ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4; (Microbial infection) The ESCRT machinery functions in topologically equivalent membrane fission events, such as the budding of enveloped viruses (HIV-1 and other lentiviruses). Involved in HIV-1 p6- and p9-dependent virus release.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Pyroptosis (R-HSA-5620971)
  Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729)
  HCMV Late Events (R-HSA-9610379)
  Late endosomal microautophagy (R-HSA-9615710)
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9679504)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9694676)
  Budding and maturation of HIV virion (R-HSA-162588)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia	DISKYHXL	moderate	Genetic Variation	[1]

2 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 Charged multivesicular body protein 2a (CHMP2A).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Charged multivesicular body protein 2a (CHMP2A).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Charged multivesicular body protein 2a (CHMP2A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Charged multivesicular body protein 2a (CHMP2A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Charged multivesicular body protein 2a (CHMP2A).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Charged multivesicular body protein 2a (CHMP2A).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Charged multivesicular body protein 2a (CHMP2A).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Charged multivesicular body protein 2a (CHMP2A).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Charged multivesicular body protein 2a (CHMP2A).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Charged multivesicular body protein 2a (CHMP2A).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Charged multivesicular body protein 2a (CHMP2A).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Charged multivesicular body protein 2a (CHMP2A).	[13]

References

• [1] Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation.J Biol Chem. 2019 Dec 13;294(50):18952-18966. doi: 10.1074/jbc.RA119.009432. Epub 2019 Oct 2.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 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.
• [6] 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.
• [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] 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.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] 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.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.