Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSNY9H4)

• DOT Name: Cytochrome b-c1 complex subunit 2, mitochondrial
• Synonyms: Complex III subunit 2; Core protein II; Ubiquinol-cytochrome-c reductase complex core protein 2
• Gene Name: UQCRC2
• Related Disease:
  Mitochondrial complex III deficiency nuclear type 5
  Mitochondrial disease
  Mitochondrial complex III deficiency
• UniProt ID: QCR2_HUMAN
• PDB ID: 5XTE; 5XTH; 5XTI
• Pfam ID: PF00675 ; PF05193
• Sequence:
  MKLLTRAGSFSRFYSLKVAPKVKATAAPAGAPPQPQDLEFTKLPNGLVIASLENYSPVSR
  IGLFIKAGSRYEDFSNLGTTHLLRLTSSLTTKGASSFKITRGIEAVGGKLSVTATRENMA
  YTVECLRGDVDILMEFLLNVTTAPEFRRWEVADLQPQLKIDKAVAFQNPQTHVIENLHAA
  AYRNALANPLYCPDYRIGKVTSEELHYFVQNHFTSARMALIGLGVSHPVLKQVAEQFLNM
  RGGLGLSGAKANYRGGEIREQNGDSLVHAAFVAESAVAGSAEANAFSVLQHVLGAGPHVK
  RGSNTTSHLHQAVAKATQQPFDVSAFNASYSDSGLFGIYTISQATAAGDVIKAAYNQVKT
  IAQGNLSNTDVQAAKNKLKAGYLMSVESSECFLEEVGSQALVAGSYMPPSTVLQQIDSVA
  NADIINAAKKFVSGQKSMAASGNLGHTPFVDEL
• 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. The 2 core subunits UQCRC1/QCR1 and UQCRC2/QCR2 are homologous to the 2 mitochondrial-processing peptidase (MPP) subunits beta-MPP and alpha-MPP respectively, and they seem to have preserved their MPP processing properties. May be involved in the in situ processing of UQCRFS1 into the mature Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 when incorporated into complex III (Probable).
• 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:HS06753-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 5	DISD6MPH	Strong	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[2]
Mitochondrial complex III deficiency	DISSUPJ6	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[16]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Cytochrome b-c1 complex subunit 2, mitochondrial.	[17]

References

• [1] Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. Hum Mutat. 2013 Mar;34(3):446-52. doi: 10.1002/humu.22257. Epub 2013 Jan 29.
• [2] 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.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Gene expression changes associated with cytotoxicity identified using cDNA arrays. Funct Integr Genomics. 2000 Sep;1(2):114-26.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [9] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [10] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [13] 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.
• [14] Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet. 2014 Apr 15;23(8):2106-19.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.