Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCYIS0L)

• DOT Name: Protoheme IX farnesyltransferase, mitochondrial (COX10)
• Synonyms: EC 2.5.1.141; Heme O synthase
• Gene Name: COX10
• Related Disease:
  Leigh syndrome
  Mitochondrial disease
  Alzheimer disease
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 1A
  Coronary heart disease
  Focal segmental glomerulosclerosis
  Mitochondrial complex 4 deficiency, nuclear type 3
  Renal tubular acidosis
  Leukodystrophy
  Cytochrome-c oxidase deficiency disease
  Anemia
  Hereditary neuropathy with liability to pressure palsies
  Non-insulin dependent diabetes
• UniProt ID: COX10_HUMAN
• EC Number: 2.5.1.141
• Pfam ID: PF01040
• Sequence:
  MAASPHTLSSRLLTGCVGGSVWYLERRTIQDSPHKFLHLLRNVNKQWITFQHFSFLKRMY
  VTQLNRSHNQQVRPKPEPVASPFLEKTSSGQAKAEIYEMRPLSPPSLSLSRKPNEKELIE
  LEPDSVIEDSIDVGKETKEEKRWKEMKLQVYDLPGILARLSKIKLTALVVSTTAAGFALA
  PGPFDWPCFLLTSVGTGLASCAANSINQFFEVPFDSNMNRTKNRPLVRGQISPLLAVSFA
  TCCAVPGVAILTLGVNPLTGALGLFNIFLYTCCYTPLKRISIANTWVGAVVGAIPPVMGW
  TAATGSLDAGAFLLGGILYSWQFPHFNALSWGLREDYSRGGYCMMSVTHPGLCRRVALRH
  CLALLVLSAAAPVLDITTWTFPIMALPINAYISYLGFRFYVDADRRSSRRLFFCSLWHLP
  LLLLLMLTCKRPSGGGDAGPPPS
• Function: Converts protoheme IX and farnesyl diphosphate to heme O.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Thermogenesis (hsa04714)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS00191-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[4]
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Strong	Biomarker	[5]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[6]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[7]
Mitochondrial complex 4 deficiency, nuclear type 3	DISLEHQO	Strong	Autosomal recessive	[8]
Renal tubular acidosis	DISE1NDR	Strong	Genetic Variation	[9]
Leukodystrophy	DISVY1TT	moderate	Genetic Variation	[10]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Supportive	Autosomal recessive	[8]
Anemia	DISTVL0C	Limited	Altered Expression	[10]
Hereditary neuropathy with liability to pressure palsies	DISY0X1V	Limited	Genetic Variation	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[12]

3 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 Protoheme IX farnesyltransferase, mitochondrial (COX10).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[21]

12 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 Protoheme IX farnesyltransferase, mitochondrial (COX10).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[25]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[26]
Farnesol	DMV2X1B	Investigative	Farnesol decreases the expression of Protoheme IX farnesyltransferase, mitochondrial (COX10).	[26]

References

• [1] Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene. Ann Neurol. 2004 Oct;56(4):560-4. doi: 10.1002/ana.20229.
• [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] Genetic association of the cytochrome c oxidase-related genes with Alzheimer's disease in Han Chinese.Neuropsychopharmacology. 2018 Oct;43(11):2264-2276. doi: 10.1038/s41386-018-0144-3. Epub 2018 Jul 6.
• [4] The Charcot-Marie-Tooth binary repeat contains a gene transcribed from the opposite strand of a partially duplicated region of the COX10 gene.Genomics. 1997 Nov 15;46(1):61-9. doi: 10.1006/geno.1997.5012.
• [5] Improved testing for CMT1A and HNPP using multiplex ligation-dependent probe amplification (MLPA) with rapid DNA preparations: comparison with the interphase FISH method.Hum Mutat. 2004 Aug;24(2):164-71. doi: 10.1002/humu.20072.
• [6] RNA-sequencing reveals that STRN, ZNF484 and WNK1 add to the value of mitochondrial MT-COI and COX10 as markers of unstable coronary artery disease.PLoS One. 2019 Dec 10;14(12):e0225621. doi: 10.1371/journal.pone.0225621. eCollection 2019.
• [7] Deletion of the Mitochondrial Complex-IV Cofactor Heme A:Farnesyltransferase Causes Focal Segmental Glomerulosclerosis and Interferon Response.Am J Pathol. 2018 Dec;188(12):2745-2762. doi: 10.1016/j.ajpath.2018.08.018. Epub 2018 Sep 28.
• [8] A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000 May 1;9(8):1245-9. doi: 10.1093/hmg/9.8.1245.
• [9] Sideroblastic anemia associated with multisystem mitochondrial disorders.Pediatr Blood Cancer. 2019 Apr;66(4):e27591. doi: 10.1002/pbc.27591. Epub 2018 Dec 26.
• [10] Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.Hum Mol Genet. 2003 Oct 15;12(20):2693-702. doi: 10.1093/hmg/ddg284. Epub 2003 Aug 19.
• [11] The human COX10 gene is disrupted during homologous recombination between the 24 kb proximal and distal CMT1A-REPs.Hum Mol Genet. 1997 Sep;6(9):1595-603. doi: 10.1093/hmg/6.9.1595.
• [12] Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes.Diabetologia. 2012 Feb;55(2):340-8. doi: 10.1007/s00125-011-2377-0. Epub 2011 Nov 18.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [26] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.