Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLQNJC7)

• DOT Name: Cytochrome b-c1 complex subunit 8
• Synonyms: Complex III subunit 8; Complex III subunit VIII; Ubiquinol-cytochrome c reductase complex 9.5 kDa protein; Ubiquinol-cytochrome c reductase complex ubiquinone-binding protein QP-C
• Gene Name: UQCRQ
• Related Disease:
  Mitochondrial complex III deficiency nuclear type 4
  Mitochondrial complex III deficiency
  Leigh syndrome
• UniProt ID: QCR8_HUMAN
• PDB ID: 5XTE; 5XTH; 5XTI
• Pfam ID: PF02939
• Sequence:
  MGREFGNLTRMRHVISYSLSPFEQRAYPHVFTKGIPNVLRRIRESFFRVVPQFVVFYLIY
  TWGTEEFERSKRKNPAAYENDK
• Function: Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Cardiac muscle contraction (hsa04260)
  Thermogenesis (hsa04714)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway: Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS09077-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex III deficiency nuclear type 4	DISI1EBK	Strong	Autosomal recessive	[1]
Mitochondrial complex III deficiency	DISSUPJ6	Supportive	Autosomal recessive	[2]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[3]

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 Cytochrome b-c1 complex subunit 8.	[4]

13 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 Cytochrome b-c1 complex subunit 8.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Cytochrome b-c1 complex subunit 8.	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome b-c1 complex subunit 8.	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome b-c1 complex subunit 8.	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome b-c1 complex subunit 8.	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytochrome b-c1 complex subunit 8.	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome b-c1 complex subunit 8.	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome b-c1 complex subunit 8.	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytochrome b-c1 complex subunit 8.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytochrome b-c1 complex subunit 8.	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytochrome b-c1 complex subunit 8.	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cytochrome b-c1 complex subunit 8.	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Cytochrome b-c1 complex subunit 8.	[17]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet. 2008 May;82(5):1211-6. doi: 10.1016/j.ajhg.2008.03.020. Epub 2008 Apr 24.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] 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.
• [5] 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.
• [6] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [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] 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.
• [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] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):216-24.