Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0962IM)

• DOT Name: Cytochrome c1, heme protein, mitochondrial (CYC1)
• Synonyms: EC 7.1.1.8; Complex III subunit 4; Complex III subunit IV; Cytochrome b-c1 complex subunit 4; Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit; Cytochrome c-1
• Gene Name: CYC1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Malaria
  Mitochondrial complex III deficiency nuclear type 6
  Adult glioblastoma
  Anaplastic astrocytoma
  Autosomal dominant optic atrophy, classic form
  Bone osteosarcoma
  Estrogen-receptor positive breast cancer
  Glioblastoma multiforme
  Glioma
  Hyperglycemia
  Neoplasm
  Osteosarcoma
  Polycystic ovarian syndrome
  Meningioma
  Metastatic malignant neoplasm
  Mitochondrial disease
  Mitochondrial complex III deficiency
  Ductal breast carcinoma in situ
  Parkinson disease
  Type-1/2 diabetes
• UniProt ID: CY1_HUMAN
• PDB ID: 5XTE; 5XTH; 5XTI
• EC Number: 7.1.1.8
• Pfam ID: PF02167
• Sequence:
  MAAAAASLRGVVLGPRGAGLPGARARGLLCSARPGQLPLRTPQAVALSSKSGLSRGRKVM
  LSALGMLAAGGAGLAMALHSAVSASDLELHPPSYPWSHRGLLSSLDHTSIRRGFQVYKQV
  CASCHSMDFVAYRHLVGVCYTEDEAKELAAEVEVQDGPNEDGEMFMRPGKLFDYFPKPYP
  NSEAARAANNGALPPDLSYIVRARHGGEDYVFSLLTGYCEPPTGVSLREGLYFNPYFPGQ
  AIAMAPPIYTDVLEFDDGTPATMSQIAKDVCTFLRWASEPEHDHRKRMGLKMLMMMALLV
  PLVYTIKRHKWSVLKSRKLAYRPPK
• 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. Cytochrome c1 is a catalytic core subunit containing a c-type heme. It transfers electrons from the [2Fe-2S] iron-sulfur cluster of the Rieske protein 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)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:HS11349-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Mitochondrial complex III deficiency nuclear type 6	DIS7DHVL	Definitive	Autosomal recessive	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Anaplastic astrocytoma	DISSBE0K	Strong	Altered Expression	[4]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Genetic Variation	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[6]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hyperglycemia	DIS0BZB5	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[6]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[7]
Meningioma	DISPT4TG	moderate	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[9]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[10]
Mitochondrial complex III deficiency	DISSUPJ6	Supportive	Autosomal recessive	[3]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Biomarker	[11]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[13]

12 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 c1, heme protein, mitochondrial (CYC1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[21]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[22]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[23]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytochrome c1, heme protein, mitochondrial (CYC1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytochrome c1, heme protein, mitochondrial (CYC1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome c1, heme protein, mitochondrial (CYC1).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cytochrome c1, heme protein, mitochondrial (CYC1).	[26]

References

• [1] Cytochrome c1 as a favorable prognostic marker in estrogen receptor-positive breast carcinoma.Histol Histopathol. 2019 Dec;34(12):1365-1375. doi: 10.14670/HH-18-130. Epub 2019 May 31.
• [2] The Malaria Parasite Cyclin H Homolog PfCyc1 Is Required for Efficient Cytokinesis in Blood-Stage Plasmodium falciparum.mBio. 2017 Jun 13;8(3):e00605-17. doi: 10.1128/mBio.00605-17.
• [3] Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia. Am J Hum Genet. 2013 Aug 8;93(2):384-9. doi: 10.1016/j.ajhg.2013.06.015. Epub 2013 Aug 1.
• [4] Selection of suitable reference genes for expression analysis in human glioma using RT-qPCR.J Neurooncol. 2015 May;123(1):35-42. doi: 10.1007/s11060-015-1772-7. Epub 2015 Apr 11.
• [5] Fluoride-induced renal dysfunction via respiratory chain complex abnormal expression and fusion elevation in mice.Chemosphere. 2020 Jan;238:124607. doi: 10.1016/j.chemosphere.2019.124607. Epub 2019 Aug 17.
• [6] MicroRNA-661 Enhances TRAIL or STS Induced Osteosarcoma Cell Apoptosis by Modulating the Expression of Cytochrome c1.Cell Physiol Biochem. 2017;41(5):1935-1946. doi: 10.1159/000472380. Epub 2017 Apr 7.
• [7] Variation in stability of housekeeping genes in endometrium of healthy and polycystic ovarian syndrome women.Hum Reprod. 2012 Jan;27(1):251-6. doi: 10.1093/humrep/der363. Epub 2011 Nov 3.
• [8] Validation of Reference Genes for Expression Studies in Human Meningiomas under Different Experimental Settings.Mol Neurobiol. 2018 Jul;55(7):5787-5797. doi: 10.1007/s12035-017-0800-3. Epub 2017 Oct 27.
• [9] CYC1 Predicts Poor Prognosis in Patients with Breast Cancer.Dis Markers. 2016;2016:3528064. doi: 10.1155/2016/3528064. Epub 2016 Apr 28.
• [10] 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.
• [11] Cytochrome c1 in ductal carcinoma in situ of breast associated with proliferation and comedo necrosis.Cancer Sci. 2017 Jul;108(7):1510-1519. doi: 10.1111/cas.13251. Epub 2017 May 19.
• [12] Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.Genet Med. 2011 May;13(5):392-9. doi: 10.1097/GIM.0b013e3182064362.
• [13] Identification of reference housekeeping-genes for mRNA expression studies in patients with type 1 diabetes.Mol Cell Biochem. 2016 Jun;417(1-2):49-56. doi: 10.1007/s11010-016-2712-3. Epub 2016 May 9.
• [14] 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.
• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [16] Gene expression changes associated with cytotoxicity identified using cDNA arrays. Funct Integr Genomics. 2000 Sep;1(2):114-26.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] 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.
• [22] 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.
• [23] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [24] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [25] 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.
• [26] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [27] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.