Details of Drug Off-Target (DOT)

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

• DOT Name: Heme A synthase COX15 (COX15)
• Synonyms: HAS; EC 1.17.99.9; Cytochrome c oxidase assembly protein COX15 homolog
• Gene Name: COX15
• Related Disease:
  Leigh syndrome
  Mitochondrial disease
  Alzheimer disease
  Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
  Cytochrome-c oxidase deficiency disease
  Cardiomyopathy
  Obsolete Leigh syndrome with leukodystrophy
  Hypertrophic cardiomyopathy
  Nervous system disease
• UniProt ID: COX15_HUMAN
• EC Number: 1.17.99.9
• Pfam ID: PF02628
• Sequence:
  MQRLLFPPLRALKGRQYLPLLAPRAAPRAQCDCIRRPLRPGQYSTISEVALQSGRGTVSL
  PSKAAERVVGRWLLVCSGTVAGAVILGGVTRLTESGLSMVDWHLIKEMKPPTSQEEWEAE
  FQRYQQFPEFKILNHDMTLTEFKFIWYMEYSHRMWGRLVGLVYILPAAYFWRKGWLSRGM
  KGRVLALCGLVCFQGLLGWYMVKSGLEEKSDSHDIPRVSQYRLAAHLGSALVLYCASLWT
  SLSLLLPPHKLPETHQLLQLRRFAHGTAGLVFLTALSGAFVAGLDAGLVYNSFPKMGESW
  IPEDLFTFSPILRNVFENPTMVQFDHRILGITSVTAITVLYFLSRRIPLPRRTKMAAVTL
  LALAYTQVGLGISTLLMYVPTPLAATHQSGSLALLTGALWLMNELRRVPK
• Function: Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO). Heme A is synthesized from heme B by two sequential enzymatic reactions catalyzed by heme O synthase (HOS) and heme A synthase (HAS). HAS catalyzes the conversion of heme O to heme A by two successive hydroxylations of the methyl group at C8, in a reaction that involves matrix ferredoxin and ferredoxin reductase. The first hydroxylation forms heme I, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme A.
• Tissue Specificity: Predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle, heart, and brain.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Thermogenesis (hsa04714)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)

Molecular Interaction Atlas (MIA) of This DOT

9 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]
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2	DIS5RVGK	Strong	Autosomal recessive	[4]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Genetic Variation	[4]
Cardiomyopathy	DISUPZRG	moderate	Genetic Variation	[4]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[5]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[6]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Heme A synthase COX15 (COX15) affects the response to substance of Warfarin.	[22]

13 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 Heme A synthase COX15 (COX15).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Heme A synthase COX15 (COX15).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heme A synthase COX15 (COX15).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Heme A synthase COX15 (COX15).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heme A synthase COX15 (COX15).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Heme A synthase COX15 (COX15).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heme A synthase COX15 (COX15).	[14]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Heme A synthase COX15 (COX15).	[15]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Heme A synthase COX15 (COX15).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Heme A synthase COX15 (COX15).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heme A synthase COX15 (COX15).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Heme A synthase COX15 (COX15).	[20]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Heme A synthase COX15 (COX15).	[21]

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 increases the methylation of Heme A synthase COX15 (COX15).	[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] 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] Analysis of the genes coding for subunit 10 and 15 of cytochrome c oxidase in Alzheimer's disease.J Neural Transm (Vienna). 2009 Dec;116(12):1635-41. doi: 10.1007/s00702-009-0324-8. Epub 2009 Oct 14.
• [4] Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency. J Med Genet. 2005 May;42(5):e28. doi: 10.1136/jmg.2004.029926.
• [5] Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome. J Med Genet. 2004 Jul;41(7):540-4. doi: 10.1136/jmg.2003.017426.
• [6] 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.
• [7] Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes.J Biol Chem. 2016 May 6;291(19):10411-25. doi: 10.1074/jbc.M115.707539. Epub 2016 Mar 3.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [16] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [17] 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.
• [18] 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.
• [19] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [21] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [22] Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array. Pharmacogenomics. 2017 Jul;18(11):1059-1073. doi: 10.2217/pgs-2017-0046. Epub 2017 Jul 7.