Ubiquinol biosynthesis (Homo sapiens)

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12, 16, 171, 35, 7-92, 314154, 1310, 11154, 6, 13mitochondrial matrixmitochondrial intermembrane spaceNADPHH+O2FAD PDSS1/2 tetramerNADPHCOQ3(?-369)IPPPAdoHcyH+PDSS2 NADPHCOQ5H2OCO2COQ2NADP+O2Mg2+ PDSS1 MDMQ10H2H+DMQ10H2NADP+PPiAdoHcyH+COQ6 Q10H2DeMQ10H2AdoHcyH+COQ9 O2H2OCOQ9 dimer:COQ7:Fe2+H2OCOQ6:FADAdoMetall-E-10PrP2MHDB decarboxylasePPiFPPH+COQ7 DHBDHDBDMPhOHMHDBNADP+PHBFe2+ DMPhOH monooxygenaseAdoMetAdoMetCOQ3(?-369)


The length of the polyisoprenoid chain of ubiquinone aka coenzyme Q (Q), varies depending on the species involved: it is 6 in budding yeast, Saccharomyces cerevisiae, (Q6) and 10 in humans (Q10). Most ubiquinone is naturally reduced to ubiquinol (Q10H2 in humans) and it is this form which dominates in most human tissues. It functions as an ubiquitous coenzyme in redox reactions and its ability both to associate with complexes I and III of the electron transport chain and to move freely in the inner mitochondrial membrane are central to its role in electron transport. In eukaryotes ubiquinones/ubiquinols are also found in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes and peroxisomes.

Ubiquinol/ubiquinone is synthesized in the following way. Initially, the polyisoprenoid tail is assembled by a polyprenyl diphosphate synthase. Next, 4 hydroxybenzoate polyprenyltransferase (COQ2) catalyses the formation of the covalent linkage between the benzoquinone head group and the tail to produce 4 hydroxy 3 polyprenyl benzoic acid intermediate (DHB, 3 decaprenyl 4 hydroxybenzoic acid in humans). There follows modifications of the aromatic ring starting with hydroxylation, followed by O methylation, and decarboxylation to form the 2 methoxy 6 polyprenyl phenol intermediate (DMPhOH ; 2 methoxy 6 decaprenylphenol in humans). Following this, two additional methylations, one C methylation, and one O methylation step, finally generate the fully substituted hydroquinone, ubiquinol (Szkopinska 2000, Kagan & Quinn 2000, Tran & Clarke 2007, Kawamukai 2009).

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Pathway is converted from Reactome ID: 2142789
Reactome version: 66
Reactome Author 
Reactome Author: Williams, MG

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  1. Saiki R, Nagata A, Kainou T, Matsuda H, Kawamukai M.; ''Characterization of solanesyl and decaprenyl diphosphate synthases in mice and humans.''; PubMed Europe PMC
  2. Forsgren M, Attersand A, Lake S, Grünler J, Swiezewska E, Dallner G, Climent I.; ''Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ.''; PubMed Europe PMC
  3. Tekle M, Turunen M, Dallner G, Chojnacki T, Swiezewska E.; ''Investigation of coenzyme Q biosynthesis in human fibroblast and HepG2 cells.''; PubMed Europe PMC
  4. Ozeir M, Mühlenhoff U, Webert H, Lill R, Fontecave M, Pierrel F.; ''Coenzyme Q biosynthesis: Coq6 is required for the C5-hydroxylation reaction and substrate analogs rescue Coq6 deficiency.''; PubMed Europe PMC
  5. Vajo Z, King LM, Jonassen T, Wilkin DJ, Ho N, Munnich A, Clarke CF, Francomano CA.; ''Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: a gene required for ubiquinone biosynthesis with potential implications for aging.''; PubMed Europe PMC
  6. Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rötig A, Nürnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Müller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocaña C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nürnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F.; ''COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.''; PubMed Europe PMC
  7. Lohman DC, Forouhar F, Beebe ET, Stefely MS, Minogue CE, Ulbrich A, Stefely JA, Sukumar S, Luna-Sánchez M, Jochem A, Lew S, Seetharaman J, Xiao R, Wang H, Westphall MS, Wrobel RL, Everett JK, Mitchell JC, López LC, Coon JJ, Tong L, Pagliarini DJ.; ''Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis.''; PubMed Europe PMC
  8. Marbois BN, Clarke CF.; ''The COQ7 gene encodes a protein in saccharomyces cerevisiae necessary for ubiquinone biosynthesis.''; PubMed Europe PMC
  9. Tran UC, Marbois B, Gin P, Gulmezian M, Jonassen T, Clarke CF.; ''Complementation of Saccharomyces cerevisiae coq7 mutants by mitochondrial targeting of the Escherichia coli UbiF polypeptide: two functions of yeast Coq7 polypeptide in coenzyme Q biosynthesis.''; PubMed Europe PMC
  10. Casey J, Threlfall DR.; ''Synthesis of 5-demethoxyubiquinone-6 and ubiquinone-6 from 3-hexaprenyl-4-hydroxybenzoate in yeast mitochondria.''; PubMed Europe PMC
  11. Goewert RR, Sippel CJ, Grimm MF, Olson RE.; ''Identification of 3-methoxy-4-hydroxy-5-hexaprenylbenzoic acid as a new intermediate in ubiquinone biosynthesis by Saccharomyces cerevisiae.''; PubMed Europe PMC
  12. Szkopińska A.; ''Ubiquinone. Biosynthesis of quinone ring and its isoprenoid side chain. Intracellular localization.''; PubMed Europe PMC
  13. Gin P, Hsu AY, Rothman SC, Jonassen T, Lee PT, Tzagoloff A, Clarke CF.; ''The Saccharomyces cerevisiae COQ6 gene encodes a mitochondrial flavin-dependent monooxygenase required for coenzyme Q biosynthesis.''; PubMed Europe PMC
  14. Barkovich RJ, Shtanko A, Shepherd JA, Lee PT, Myles DC, Tzagoloff A, Clarke CF.; ''Characterization of the COQ5 gene from Saccharomyces cerevisiae. Evidence for a C-methyltransferase in ubiquinone biosynthesis.''; PubMed Europe PMC
  15. Jonassen T, Clarke CF.; ''Isolation and functional expression of human COQ3, a gene encoding a methyltransferase required for ubiquinone biosynthesis.''; PubMed Europe PMC
  16. Tran UC, Clarke CF.; ''Endogenous synthesis of coenzyme Q in eukaryotes.''; PubMed Europe PMC
  17. Kawamukai M.; ''Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms.''; PubMed Europe PMC


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101289view11:17, 1 November 2018ReactomeTeamreactome version 66
100826view20:48, 31 October 2018ReactomeTeamreactome version 65
100367view19:23, 31 October 2018ReactomeTeamreactome version 64
99914view16:07, 31 October 2018ReactomeTeamreactome version 63
99469view14:39, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93797view13:37, 16 August 2017ReactomeTeamreactome version 61
93334view11:20, 9 August 2017ReactomeTeamreactome version 61
87196view10:21, 19 July 2016EgonwOntology Term : 'lipid metabolic pathway' added !
87195view10:20, 19 July 2016EgonwOntology Term : 'classic metabolic pathway' added !
86421view09:17, 11 July 2016ReactomeTeamreactome version 56
83140view10:08, 18 November 2015ReactomeTeamVersion54
81483view13:01, 21 August 2015ReactomeTeamVersion53
76961view08:24, 17 July 2014ReactomeTeamFixed remaining interactions
76666view12:03, 16 July 2014ReactomeTeamFixed remaining interactions
75995view10:05, 11 June 2014ReactomeTeamRe-fixing comment source
75698view11:03, 10 June 2014ReactomeTeamReactome 48 Update
75054view13:56, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74698view08:46, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
COQ2ProteinQ96H96 (Uniprot-TrEMBL)
COQ3(?-369)ProteinQ9NZJ6 (Uniprot-TrEMBL)
COQ5ProteinQ5HYK3 (Uniprot-TrEMBL)
COQ6 ProteinQ9Y2Z9 (Uniprot-TrEMBL)
COQ6:FADComplexR-HSA-2162308 (Reactome)
COQ7 ProteinQ99807 (Uniprot-TrEMBL)
COQ9 ProteinO75208 (Uniprot-TrEMBL)
COQ9 dimer:COQ7:Fe2+ComplexR-HSA-8933003 (Reactome)
DHBMetaboliteCHEBI:64136 (ChEBI)
DHDBMetaboliteCHEBI:50775 (ChEBI)
DMPhOH monooxygenaseR-HSA-2167826 (Reactome)
DMPhOHMetaboliteCHEBI:50774 (ChEBI)
DMQ10H2MetaboliteCHEBI:64181 (ChEBI)
DeMQ10H2MetaboliteCHEBI:64182 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FPPMetaboliteCHEBI:17407 (ChEBI)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
IPPPMetaboliteCHEBI:16584 (ChEBI)
MDMQ10H2MetaboliteCHEBI:64180 (ChEBI)
MHDB decarboxylaseR-HSA-2167848 (Reactome)
MHDBMetaboliteCHEBI:50776 (ChEBI)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PDSS1 ProteinQ5T2R2 (Uniprot-TrEMBL)
PDSS1/2 tetramerComplexR-HSA-2162271 (Reactome)
PDSS2 ProteinQ86YH6 (Uniprot-TrEMBL)
PHBMetaboliteCHEBI:30763 (ChEBI)
PPiMetaboliteCHEBI:29888 (ChEBI)
Q10H2MetaboliteCHEBI:64183 (ChEBI)
all-E-10PrP2MetaboliteCHEBI:61011 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-2162186 (Reactome)
AdoHcyArrowR-HSA-2162188 (Reactome)
AdoHcyArrowR-HSA-2162193 (Reactome)
AdoMetR-HSA-2162186 (Reactome)
AdoMetR-HSA-2162188 (Reactome)
AdoMetR-HSA-2162193 (Reactome)
CO2ArrowR-HSA-2162195 (Reactome)
COQ2mim-catalysisR-HSA-2162192 (Reactome)
COQ3(?-369)mim-catalysisR-HSA-2162186 (Reactome)
COQ3(?-369)mim-catalysisR-HSA-2162193 (Reactome)
COQ5mim-catalysisR-HSA-2162188 (Reactome)
COQ6:FADmim-catalysisR-HSA-2162187 (Reactome)
COQ9 dimer:COQ7:Fe2+mim-catalysisR-HSA-2162194 (Reactome)
DHBArrowR-HSA-2162192 (Reactome)
DHBR-HSA-2162187 (Reactome)
DHDBArrowR-HSA-2162187 (Reactome)
DHDBR-HSA-2162193 (Reactome)
DMPhOH monooxygenasemim-catalysisR-HSA-2162191 (Reactome)
DMPhOHArrowR-HSA-2162195 (Reactome)
DMPhOHR-HSA-2162191 (Reactome)
DMQ10H2ArrowR-HSA-2162188 (Reactome)
DMQ10H2R-HSA-2162194 (Reactome)
DeMQ10H2ArrowR-HSA-2162194 (Reactome)
DeMQ10H2R-HSA-2162186 (Reactome)
FPPR-HSA-2162253 (Reactome)
H+ArrowR-HSA-2162186 (Reactome)
H+ArrowR-HSA-2162188 (Reactome)
H+ArrowR-HSA-2162193 (Reactome)
H+R-HSA-2162187 (Reactome)
H+R-HSA-2162191 (Reactome)
H+R-HSA-2162194 (Reactome)
H2OArrowR-HSA-2162187 (Reactome)
H2OArrowR-HSA-2162191 (Reactome)
H2OArrowR-HSA-2162194 (Reactome)
IPPPR-HSA-2162253 (Reactome)
MDMQ10H2ArrowR-HSA-2162191 (Reactome)
MDMQ10H2R-HSA-2162188 (Reactome)
MHDB decarboxylasemim-catalysisR-HSA-2162195 (Reactome)
MHDBArrowR-HSA-2162193 (Reactome)
MHDBR-HSA-2162195 (Reactome)
NADP+ArrowR-HSA-2162187 (Reactome)
NADP+ArrowR-HSA-2162191 (Reactome)
NADP+ArrowR-HSA-2162194 (Reactome)
NADPHR-HSA-2162187 (Reactome)
NADPHR-HSA-2162191 (Reactome)
NADPHR-HSA-2162194 (Reactome)
O2R-HSA-2162187 (Reactome)
O2R-HSA-2162191 (Reactome)
O2R-HSA-2162194 (Reactome)
PDSS1/2 tetramermim-catalysisR-HSA-2162253 (Reactome)
PHBR-HSA-2162192 (Reactome)
PPiArrowR-HSA-2162192 (Reactome)
PPiArrowR-HSA-2162253 (Reactome)
Q10H2ArrowR-HSA-2162186 (Reactome)
R-HSA-2162186 (Reactome) Mitochondrial COQ3 is an O-methyltransferase required in the reaction to convert 3-demethylubiquinol-10 (DeMQ10H2) to ubiquinol-10 (Q10H2) (Jonassen & Clarke 2000).
R-HSA-2162187 (Reactome) A flavin-dependent monooxygenase involved in ubiquinone/ubiquinol biosynthesis, COQ6 (Heeringa et al. 2011) catalyses the C5-hydroxylation of 3-decaprenyl-4-hydroxybenzoic acid (DHB) to 3,4-dihydroxy-5-decaprenylbenzoic acid (DHDB). COQ6 is a peripheral membrane protein that localizes to the matrix side of the inner mitochondrial membrane (Gin et al. 2003). This reaction involving COQ6 is inferred from the equivalent reaction in yeast (Ozeir et al. 2011, Gin et al. 2003).
R-HSA-2162188 (Reactome) 2-methoxy-6-polyprenyl-1,4-benzoquinol methylase, mitochondrial (COQ5) catalyses the C-methyltransferase conversion of 2-methoxy-6-decaprenyl-1,4-benzoquinol (MDMQ10H2) to 6-methoxy-3-methyl-2-decaprenyl-1,4-benzoquinol (DMQ10H2). This reaction is inferred from the equivalent reaction in yeast (Barkovich et al. 1997).
R-HSA-2162191 (Reactome) 2-methoxy-6-decaprenylphenol (DMPhOH) is enzymatically converted to 2-methoxy-6-decaprenyl-1,4-benzoquinol (MDMQ10H2). It was thought at one time that the flavin-dependent monooxygenase, COQ6, was the enzyme that catalysed this reaction, however, it has been subsequently shown that COQ6 is not essential for this reaction (Ozeir et al. 2011). However, it is still believed that another member of the COQ family catalyses this event. This reaction is inferred from the equivalent reaction in yeast (Gin et al. 2003, Ozeir et al. 2011).
R-HSA-2162192 (Reactome) 4-hydroxybenzoate polyprenyltransferase, mitochondrial (COQ2) catalyses the combination of 4-hydroxybenzoic acid, aka para-hydroxybenzoic acid (PHB) with the polyisoprenoid tail all-trans-decaprenyl diphosphate (all-E-10PrP2) to form 3-decaprenyl-4-hydroxybenzoic acid (DHB) (Forsgren et a l. 2004, Tekle et al. 2008). This reaction is irreversible and occurs in the mitochondria.
R-HSA-2162193 (Reactome) Mitochondrial COQ3 is an O-methyltransferase required in the reaction to convert 3,4-dihydroxy-5-decaprenylbenzoic acid (DHDB) to 3-methoxy-4-hydroxy-5-decaprenylbenzoic acid (MHDB) (Jonassen & Clarke 2000).
R-HSA-2162194 (Reactome) Ubiquinone biosynthesis protein COQ7 homolog (COQ7) (Vajo et al. 1999) catalyses the hydroxylation of 6-methoxy-3-methyl-2-decaprenyl-1,4-benzoquinol (DMQ10H2) to 3-demethylubiquinol-10 (DeMQ10H2). This reaction is inferred from the equivalent reaction in yeast (Marbois & Clarke 1996, Tran et al. 2006). Mitochondrial ubiquinone biosynthesis protein COQ9 is a lipid-binding protein involved in the biosynthesis of coenzyme Q. It binds with COQ7, an interaction that may be necessary to present the lipid to COQ7 activity (Lohman et al. 2014).
R-HSA-2162195 (Reactome) 3-methoxy-4-hydroxy-5-decaprenylbenzoic acid (MHDB) is enzymatically decarboxylated to form 2-methoxy-6-decaprenylphenol (DMPhOH). At the present time the enzyme identity is unknown but is thought to be a member of the COQ family. This reaction is inferred from the equivalent reaction in yeast (Casey & Threlfall 1978, Goewert et al. 1981).
R-HSA-2162253 (Reactome) The polyprenyl diphosphate synthase consists of a tetramer comprising two units of decaprenyl-diphosphate synthase subunit 1 (PDSS1) and two units of decaprenyl-diphosphate synthase subunit 2 (PDSS2). It catalyses the combination of 2-trans,6-trans-farnesyl diphosphate (FPP) with isopentenyl diphosphate (IPPP) to form the polyisoprenoid tail all-trans-decaprenyl diphosphate (all-E-10PrP2) (Saiki et al. 2005, Tekle et al. 2008).
all-E-10PrP2ArrowR-HSA-2162253 (Reactome)
all-E-10PrP2R-HSA-2162192 (Reactome)
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