Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDAKEY4)

• DOT Name: 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2)
• Synonyms: 4-HB polyprenyltransferase; EC 2.5.1.39; 4-hydroxybenzoate decaprenyltransferase; COQ2 homolog; hCOQ2; Para-hydroxybenzoate--polyprenyltransferase; PHB:PPT; PHB:polyprenyltransferase
• Gene Name: COQ2
• Related Disease:
  Coenzyme Q10 deficiency, primary, 1
  Mitochondrial disease
  Alzheimer disease
  Coenzyme Q10 deficiency
  Metabolic myopathy
  Myositis disease
  Nephropathy
  Nephrotic syndrome
  Neuromuscular disease
  Parasitic infection
  Parkinsonian disorder
  Plasmodium vivax malaria
  Steroid-resistant nephrotic syndrome
  Multiple system atrophy
  Obsolete Leigh syndrome with nephrotic syndrome
  Anemia
  Malaria
  Striatonigral degeneration
• UniProt ID: COQ2_HUMAN
• EC Number: 2.5.1.39
• Pfam ID: PF01040
• Sequence:
  MLGSRAAGFARGLRAVALAWLPGWRGRSFALARAAGAPHGGDLQPPACPEPRGRQLSLSA
  AAVVDSAPRPLQPYLRLMRLDKPIGTWLLYLPCTWSIGLAAEPGCFPDWYMLSLFGTGAI
  LMRGAGCTINDMWDQDYDKKVTRTANRPIAAGDISTFQSFVFLGGQLTLALGVLLCLNYY
  SIALGAGSLLLVITYPLMKRISYWPQLALGLTFNWGALLGWSAIKGSCDPSVCLPLYFSG
  VMWTLIYDTIYAHQDKRDDVLIGLKSTALRFGENTKPWLSGFSVAMLGALSLVGVNSGQT
  APYYAALGAVGAHLTHQIYTLDIHRPEDCWNKFISNRTLGLIVFLGIVLGNLWKEKKTDK
  TKKGIENKIEN
• Function: Mediates the second step in the final reaction sequence of coenzyme Q (CoQ) biosynthesis. Catalyzes the prenylation of para-hydroxybenzoate (PHB) with an all-trans polyprenyl donor (such as all-trans-decaprenyl diphosphate). The length of the polyprenyl side chain varies depending on the species, in humans, the side chain is comprised of 10 isoprenyls (decaprenyl) producing CoQ10 (also known as ubiquinone), whereas rodents predominantly generate CoQ9. However, this specificity is not complete, human tissues have low amounts of CoQ9 and rodent organs contain some CoQ10. Plays a central role in the biosynthesis of CoQ10. CoQ10 is a vital molecule that transports electrons from mitochondrial respiratory chain complexes. CoQs also function as cofactors for uncoupling protein and play a role as regulators of the extracellularly-induced ceramide-dependent apoptotic pathway. Regulates mitochondrial permeability transition pore (mPTP) opening and ROS production (pivotal events in cell death) in a tissue specific manner.
• Tissue Specificity: Widely expressed. Present in all of the tissues tested. Expressed at higher level in skeletal muscle, adrenal glands and the heart.
• KEGG Pathway:
  Ubiquinone and other terpenoid-quinone biosynthesis (hsa00130)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  Ubiquinol biosynthesis (R-HSA-2142789)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:ENSG00000173085-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coenzyme Q10 deficiency, primary, 1	DISD9V13	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[4]
Metabolic myopathy	DISSE3BW	Strong	Biomarker	[5]
Myositis disease	DISCIXF0	Strong	Biomarker	[5]
Nephropathy	DISXWP4P	Strong	Biomarker	[4]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[6]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[5]
Parasitic infection	DISX9CEW	Strong	Biomarker	[7]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[8]
Plasmodium vivax malaria	DISPU3H9	Strong	Biomarker	[9]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Genetic Variation	[4]
Multiple system atrophy	DISASEYE	Moderate	Autosomal recessive	[10]
Obsolete Leigh syndrome with nephrotic syndrome	DIS4M8RK	Supportive	Autosomal recessive	[11]
Anemia	DISTVL0C	Limited	Genetic Variation	[12]
Malaria	DISQ9Y50	Limited	Genetic Variation	[13]
Striatonigral degeneration	DIS0NDAM	Limited	SusceptibilityMutation	[14]

9 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 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[21]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[25]

2 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 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2).	[24]

References

• [1] Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J Clin Invest. 2007 Mar;117(3):765-72. doi: 10.1172/JCI29089.
• [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] Lack of association of mortalin (HSPA9) and other mitochondria-related genes with risk of Parkinson's and Alzheimer's diseases.Neurobiol Aging. 2017 Jan;49:215.e9-215.e10. doi: 10.1016/j.neurobiolaging.2016.09.017. Epub 2016 Oct 3.
• [4] A steroid-resistant nephrotic syndrome in an infant resulting from a consanguineous marriage with COQ2 and ARSB gene mutations: a case report.BMC Med Genet. 2019 Oct 28;20(1):165. doi: 10.1186/s12881-019-0898-4.
• [5] Iatrogenic myopathies.Curr Opin Neurol. 2010 Oct;23(5):445-9. doi: 10.1097/WCO.0b013e32833c2054.
• [6] COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.Pediatr Nephrol. 2018 Jul;33(7):1257-1261. doi: 10.1007/s00467-018-3937-z. Epub 2018 Apr 10.
• [7] A four-antigen mixture for rapid assessment of Onchocerca volvulus infection.PLoS Negl Trop Dis. 2009;3(5):e438. doi: 10.1371/journal.pntd.0000438. Epub 2009 May 19.
• [8] Mutation Analysis of COQ2 in Chinese Patients with Cerebellar Subtype of Multiple System Atrophy.CNS Neurosci Ther. 2015 Aug;21(8):626-30. doi: 10.1111/cns.12412. Epub 2015 Jun 20.
• [9] Soluble recombinant merozoite surface antigen-142kDa of Plasmodium vivax: An improved diagnostic antigen for vivax malaria.J Microbiol Methods. 2016 Apr;123:44-50. doi: 10.1016/j.mimet.2016.02.003. Epub 2016 Feb 3.
• [10] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [11] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [12] Merozoite surface antigen 1 and 2 genotypes and rosetting of Plasmodium falciparum in severe and mild malaria in Lambarn, Gabon.Trans R Soc Trop Med Hyg. 1998 Jan-Feb;92(1):110-4. doi: 10.1016/s0035-9203(98)90979-8.
• [13] Humoral response to defined Plasmodium falciparum antigens in cerebral and uncomplicated malaria and their relationship to parasite genotype.Am J Trop Med Hyg. 1997 Apr;56(4):430-5. doi: 10.4269/ajtmh.1997.56.430.
• [14] Mutations in COQ2 in familial and sporadic multiple-system atrophy.N Engl J Med. 2013 Jul 18;369(3):233-44. doi: 10.1056/NEJMoa1212115. Epub 2013 Jun 12.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [20] Effect of mitochondrial dysfunction and oxidative stress on endogenous levels of coenzyme Q(10) in human cells. J Biochem Mol Toxicol. 2011 Sep-Oct;25(5):280-9. doi: 10.1002/jbt.20387. Epub 2011 Feb 9.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [23] 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.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.