Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP715L8)

• DOT Name: Charged multivesicular body protein 1b (CHMP1B)
• Synonyms: CHMP1.5; Chromatin-modifying protein 1b; CHMP1b; Vacuolar protein sorting-associated protein 46-2; Vps46-2; hVps46-2
• Gene Name: CHMP1B
• Related Disease:
  Clear cell renal carcinoma
  Epilepsy
  Friedreich's ataxia
  Migraine disorder
  Mitochondrial DNA depletion syndrome
  Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
  Myopathy
  Perrault syndrome
  Premature aging syndrome
  Progressive external ophthalmoplegia
  Ptosis
  Renal cell carcinoma
  Inclusion body myositis
  Intellectual disability
  Mitochondrial disease
  Parkinsonian disorder
• UniProt ID: CHM1B_HUMAN
• PDB ID: 3EAB; 3JC1; 4TXQ; 4TXR; 6E8G; 6TZ4; 6TZ5; 6TZ9
• Pfam ID: PF03357
• Sequence:
  MSNMEKHLFNLKFAAKELSRSAKKCDKEEKAEKAKIKKAIQKGNMEVARIHAENAIRQKN
  QAVNFLRMSARVDAVAARVQTAVTMGKVTKSMAGVVKSMDATLKTMNLEKISALMDKFEH
  QFETLDVQTQQMEDTMSSTTTLTTPQNQVDMLLQEMADEAGLDLNMELPQGQTGSVGTSV
  ASAEQDELSQRLARLRDQV
• 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 cytokinesis. Involved in recruiting VPS4A and/or VPS4B and SPAST to the midbody of dividing cells. Involved in HIV-1 p6- and p9-dependent virus release.
• Tissue Specificity: Widely expressed. Expressed in pancreas, kidney, skeletal muscle, liver, lung, placenta and brain.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Friedreich's ataxia	DIS5DV35	Strong	Biomarker	[3]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[2]
Mitochondrial DNA depletion syndrome	DISIGZSM	Strong	Genetic Variation	[4]
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)	DISWVOY7	Strong	Genetic Variation	[5]
Myopathy	DISOWG27	Strong	Genetic Variation	[5]
Perrault syndrome	DISG2YOV	Strong	Genetic Variation	[6]
Premature aging syndrome	DIS51AGT	Strong	Genetic Variation	[7]
Progressive external ophthalmoplegia	DISX4ATI	Strong	Genetic Variation	[8]
Ptosis	DISJZNIY	Strong	Genetic Variation	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[1]
Inclusion body myositis	DISZXXG5	moderate	Genetic Variation	[10]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[11]
Mitochondrial disease	DISKAHA3	Limited	Biomarker	[12]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[13]

8 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 1b (CHMP1B).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Charged multivesicular body protein 1b (CHMP1B).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Charged multivesicular body protein 1b (CHMP1B).	[16]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of Charged multivesicular body protein 1b (CHMP1B).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Charged multivesicular body protein 1b (CHMP1B).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Charged multivesicular body protein 1b (CHMP1B).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Charged multivesicular body protein 1b (CHMP1B).	[21]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Charged multivesicular body protein 1b (CHMP1B).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Charged multivesicular body protein 1b (CHMP1B).	[18]

References

• [1] DNA sequences proximal to human mitochondrial DNA deletion breakpoints prevalent in human disease form G-quadruplexes, a class of DNA structures inefficiently unwound by the mitochondrial replicative Twinkle helicase.J Biol Chem. 2014 Oct 24;289(43):29975-93. doi: 10.1074/jbc.M114.567073. Epub 2014 Sep 5.
• [2] Migraine and epilepsy: a focus on overlapping clinical, pathophysiological, molecular, and therapeutic aspects.Curr Pain Headache Rep. 2010 Aug;14(4):276-83. doi: 10.1007/s11916-010-0121-y.
• [3] A mitochondrial implication in a Tunisian patient with Friedreich's ataxia-like.Pathol Biol (Paris). 2014 Feb;62(1):41-8. doi: 10.1016/j.patbio.2013.07.013. Epub 2013 Sep 4.
• [4] Twinkle-Associated Mitochondrial DNA Depletion.Pediatr Neurol. 2019 Jan;90:61-65. doi: 10.1016/j.pediatrneurol.2018.08.007. Epub 2018 Aug 9.
• [5] Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy.Neurogenetics. 2014 Aug;15(3):171-82. doi: 10.1007/s10048-014-0405-1. Epub 2014 May 10.
• [6] First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.J Hum Genet. 2016 Apr;61(4):295-300. doi: 10.1038/jhg.2015.149. Epub 2015 Dec 10.
• [7] Novel mutation in C10orf2 associated with multiple mtDNA deletions, chronic progressive external ophthalmoplegia and premature aging.Mitochondrion. 2016 Jan;26:81-5. doi: 10.1016/j.mito.2015.12.006. Epub 2015 Dec 12.
• [8] Mutation in TWINKLE in a Large Iranian Family with Progressive External Ophthalmoplegia, Myopathy, Dysphagia and Dysphonia, and Behavior Change.Arch Iran Med. 2016 Feb;19(2):87-91.
• [9] Orthostatic tremor, progressive external ophthalmoplegia, and Twinkle.JAMA Neurol. 2013 Nov;70(11):1429-31. doi: 10.1001/jamaneurol.2013.3521.
• [10] Mitochondrial pathology in inclusion body myositis.Neuromuscul Disord. 2015 Apr;25(4):281-8. doi: 10.1016/j.nmd.2014.12.010. Epub 2015 Jan 6.
• [11] Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability.Metab Brain Dis. 2016 Aug;31(4):901-7. doi: 10.1007/s11011-016-9827-9. Epub 2016 Apr 28.
• [12] Defects of mitochondrial DNA replication.J Child Neurol. 2014 Sep;29(9):1216-24. doi: 10.1177/0883073814537380. Epub 2014 Jun 30.
• [13] Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art.Neurosci Lett. 2013 Nov 27;556:1-4. doi: 10.1016/j.neulet.2013.09.034. Epub 2013 Sep 26.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.