Subsystem: Ubiquinone Biosynthesis

This subsystem's description is:

Ubiquinone (Coenzyme Q) functions in the respiratory electron transport chain and serves as a lipophilic antioxidant. Ubiquinone is an acceptor of electrons from many cellular dehydrogenases involved in the oxidative metabolism of dihydroorotate, choline, fatty acyl-CoA, glycerolphosphate, sarcosine, and dimethylglycine .
The UQ biosynthetic enzymes may constitute a complex that is tightly bound to the membrane.
In the biosythetic pathway the nucleus is derived from the shikimate pathway via chorismate in bacteria or tyrosin in higher eukaryotes. The prenyl side chain is derived from prenyl diphosphate (prenyl PPi) and the methyl groups are derived from S-adenosylmethionine.

========= Variant codes:==============

(1.0) - Prokaryotes producing ubiquinone from chorismate = genes UbiC,*UbiA,*UbiD,UbiB,UbiG,*UbiH, UbiE, and *UbiF;

(1.7) - Full prokaryotic pathway without ubiD (special case of missing gene since that occures in many genomes);

(1.x) - Organisms, producing ubiquinone from chorismate, but having a missing gene in the pathway;

(2.0) - Organisms, producing ubiquinone in eucariotic way: from tyrosin or phenilalanin, so they do not need UbiC - Chorismate-pyruvate lyase(as in Saccharomyces cerevisiae):

Var.2.0 = genes UbiC,UbiA,*UbiD,UbiB,UbiG,*UbiH, UbiE, and *UbiF

UbiD missed in Schizosaccharomyces pombe [E], and in such bacteria as Xylella fastidiosa

(2.7) - Full "eucariotic-like" pathway without ubiD (special case of missing gene since that occures in many genomes);


(2.x) - Organisms, producing ubiquinone in eucariotic way(from tyrosin or phenilalanin, no Chorismate-pyruvate lyase), but having a missing gene in the pathway;

(3.0) – Organisms, not producing ubiquinone, but containing some of Ubiquinone Biosynthesis genes; Synechocystis does not contain ubiquinone, but the genes specific for enzymes of the ubiquinone pathway are still present;

UbiD is missing in a lot of eucaria ssp.

(-1) – no Ubiquinone Biosynthesis; gene ubiE is shown in some of these organisms because it’s product - Ubiquinone/menaquinone biosynthesis methyltransferase UbiE/COQ5 (EC 2.1.1.-) - participates in Menaquinone biosynthesis as well. Staphylococcus do not produce Ubiquinone but produce Menaquinone, so they have ubiE enzyme.

(0) - not clear, work in progress
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Ubiquinone (UQ)is constituted of a quinone structure and a side chain isoprenoid. The side chain length of UQ differs between microorganisms.
Abbreviations are Q or Q-n where ‘n’ refers to the number of prenyl units present in the side chain. E. coli contains Q-8 (n=8, a 40 carbon isoprenoid side chain) as the predominant quinone with minor amounts of Q-1 to Q-7 and Q-9. The predominant side chain length is a constant depending on the species.
Homo sapiens, Rhodobacter capsulatus, E. coli, and the yeast, Saccharomyces cerevisiae have side chain lengths of n=10, 9, 8, and 6, respectively.
Aerobic Gram-negative bacteria and eukaryotes contain the benzoquinone, ubiquinone, as the sole quinone, while the facultative anaerobic bacteria such as Escherichia coli contain the naphthoquinones, demethylmenaquinone (DMK) and menaquinone (MK) in addition to ubiquinone.
The archaea, as a group, lack ubiquinone.
The gram-positive organisms Bacillus subtilis and Streptomyces sp. synthesize menaquinones, and the cyanobacterium Synechocystis sp. makes plastoquinone instead of ubiquinone.

Streptococcus - do not produce Ubiquinone or Menaquinone.

Staphylococcus - do not produce Ubiquinone but produce Menaquinone, so they have ubiE enzyme.

Synechocystis - does not contain ubiquinone, but uses plastoquinone both for respiration and for photosynthesis. Nevertheless, the genes specific for enzymes of the ubiquinone pathway are still present.


Yeast seems to produce 4-hydroxybenzoate by two different ways ( see ref#1). It may be produced directly from chorismate by the chorismate pyruvate-lyase reaction similar to E. coli, or alternately from tyrosine, similar to higher eukaryotes. In animal cells, 4-hydroxybenzoate is formed from the essential amino acid tyrosine.
Consistent with the existence of two different routes is the fact that yeast mutants blocked in the formation of 4-hydroxybenzoate have never been isolated. Evidence for the presence of the two alternate routes was obtained using shikimate pathway mutants. Mutants blocked in the formation of shikimate or chorismate are expected to be deficient in the formation of Q, due to their inability to form 4-hydroxybenzoate. Addition of tyrosine to the growth medium restored the ability of these mutants to form 4-hydroxybenzoate and Q.
It was further shown that wild-type yeast normally uses the conversion of chorismate to 4-hydroxybenzoate as the source of precursor for Q. However, in the shikimate pathway mutants, tyrosine is able to compensate fully by providing the 4-hydroxybenzoate required for Q biosynthesis. It seems likely that many of the lower eukaryotes that have the shikimate pathway may contain dual pathways for the biosynthesis of 4-hydroxybenzoate.

============Saccharomyces cerevisiae:============================

Resently it was shown that the major sequence of CoQ synthesizing enzymes, products of COQ3–COQ8, is organized in a multi-subunit complex in yeast. There are eight modifications of the benzoate ring and only two mammalian genes are isolated and their enzymes partly characterized. Coq3p catalyzes two O-methylations and coq7p catalyzes one hydroxylation. The COQ5 gene has been attributed to the C-methylation of the ring and the COQ6 gene is suggested to be involved in one of the hydroxylations. COQ4 and ABC1/COQ8 have been isolated although their function is unknown.

====Explanation for some functional roles:==================

1. UbiC - The formation of 4-hydroxybenzoate from chorismate is the first committed step in the biosynthesis of UQ. This aromatizing reaction is catalyzed by the enzyme chorismate pyruvate-lyase. The ubiC gene has been overexpressed, and the enzyme purified to homogeneity and characterized.

**** in Mycobacterium:
Resently gene Rv2949c (this gene and it's homologs were annotated as hypotetical protein) was establish as a chorismate pyruvate-lyase responsible for the direct conversion of chorismate to p-hydroxybenzoate and identify Rv2949c as the sole enzymatic source of p-hydroxybenzoic acid in M. tuberculosis (see Ref.8)

2. UbiA - 4-Hydroxybenzoate polyprenyltransferase is a key enzyme in the biosynthesis of ubiquinone. It is responsible for the prenylation of 4-hydroxybenzoate using a polyprenyldiphosphate as a side chain precursor. The enzyme is non-specific and can use a variety of prenyl diphosphates as side chain precursors. The lack of specificity of the enzyme also extends to the aromatic substrate. Thus, the enzyme tolerates substitutions by various groups at different positions on the benzene ring of Q. Smaller amounts of UQs with various side chains are formed in E. coli because the prenyl transferase is relatively non-specific. The prenyl transferase incorporates geranyl-, farnesyl- and solanesyl Ppi into 4-hydroxybenzoate. The UbiA homologue COQ2 from S. cerevisiae also has limited substrate specificity.

3. UbiD, UbiX - 3-polyprenyl-4-hydroxybenzoate decarboxylase catalyzes the third reaction in ubiquinone biosynthesis. There is a second decarboxylase present in E. coli, the ubiX gene product. It is present in much lower levels than the ubiD encoded enzyme. The genes ubiD and ubiX, having no sequence homologies with each other, both encode enzymes with 3-octaprenyl-4-hydroxybenzoate lyase activities in the ubiquinone biosynthetic pathway (Ref.8). These proteins belong to a select group of approximately 200 isofunctional enzymes in E. coli. The redundancy of UbiD and UbiX proteins, occurring at the third step of the pathway, is both puzzling and intriguing.

===== The biosynthesis of Q involves at least nine reactions:=================

Three of these reactions involve hydroxylations resulting in the introduction of hydroxyl groups at positions C-6, C-4, and C-5 of the benzene nucleus of Q. The genes encoding the enzymes responsible for these hydroxylations, ubiB, ubiH, and ubiF:

4. UbiB - ( gene names: ubiB, yigR, fsrC, fre, fadI )- in E.coli - 2-octaprenylphenol 6-hydroxylase – product of gene ubiB (aarF) is believed to catalyze the first hydroxylation step in the pathway. ubiB was first discovered as a gene encoding flavin reductase . and later identified.
The functional role of the ubiB gene product in the hydroxylation of octaprenylphenol is unknown. The ubiB gene does not contain sequence identity corresponding to known monooxygenases in the databases. ubiB shares sequence identity with the ABC1 gene in S. cerevisiae, which is required for function of the mitochondrial bc1 complex. Recently, the Arabidopsis thaliana homologue of ABC1 was identified through functional complementation of a yeast ABC1 deletion mutant. Thus, the function of ABC1 in the biosynthesis of CoQ is likely to be conserved. It was shown that Abc1 and Abc1-related proteins are part of a large family of proteins in both eukaryotes and prokaryotes, including Mycobacterium tuberculosis, Mycobacterium leprae, and Clostridium pasteurianum.
Along with ABC1, ubiB is part of a large family of proteins that contain motifs found in eukaryotic-type protein kinases , although it is not known if the protein encoded by ubiB contains kinase activity or what substrates it may act on.
5. UbiH - In E.coli - 2-octaprenyl-6-methoxyphenol hydroxylase (EC 1.14.13.-). The COQ6 gene shows sequence similarity to E. coli
ubiH.
6. UbiG - In E.coli - 3-demethylubiquinone-9 3-methyltransferase (EC 2.1.1.64) / 2-octaprenyl-6-hydroxyphenol methylase .The biosynthesis of ubiquinone requires two O-methylation reactions. Recent studies have shown that one O-methyltransferase, identified as UbiG in E. coli and Coq3 in yeast, catalyzes both O-methylation steps in CoQ biosynthesis. The UbiG and UbiE amino acid sequences both contain an S-adenosylmethionine-binding motif which is shared by some, but not all, methyltransferases.
7. UbiE - The ubiE gene product, a C-methyltransferase, catalyzes reactions in both ubiquinone (Q) and menaquinone (MK) biosynthesis. Q biosynthesis and MK biosynthesis diverge after the formation of chorismate and the pathways proceed independently except for the C methylation step. In MK biosynthesis the ubiE encoded enzyme catalyzes the conversion of demethylmenaquinone to menaquinone. The corresponding C-methyltransferase in yeast was identified as COQ5 with 44% sequence identity over 262 amino acids to UbiE, which is required for a C-methyltransferase step in the Q and menaquinone biosynthetic pathways in Escherichia coli. Both the ubiE and COQ5 coding sequences contain sequence motifs common to a wide variety of S-adenosyl-L-methionine-dependent methyltransferases.


References:

1. R. Meganathan. Ubiquinone biosynthesis in microorganisms.
FEMS Microbiology Letters, Volume 203, Issue 2, 25 September 2001, pp.131-139

1a. Kwon O, Druce-Hoffman M, Meganathan R. Regulation of the ubiquinone (coenzyme Q) biosynthetic genes ubiCA in Escherichia coli. Curr Microbiol. 2005 Apr;50(4):180-9. Epub 2005 Mar 15.
PMID: 15902464 .

2. Szkopinska A. Ubiquinone. Biosynthesis of quinone ring and its isoprenoid side chain. Intracellular localization. Acta Biochim Pol. 2000;47(2):469-80. Review.

3. Makoto Kawamukai. Biosynthesis, bioproduction and novel roles of ubiquinone. Journal of Bioscience and Bioengineering, Volume 94, Issue 6, December 2002, pp. 511-517

4. Poon WW, Davis DE, Ha HT, Jonassen T, Rather PN, Clarke CF. Identification of Escherichia coli ubiB, a gene required for the first monooxygenase step in ubiquinone biosynthesis. J Bacteriol. 2000 Sep;182(18):5139-46.

5.Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004 Jan 28;1660(1-2):171-99. Review.

6.Soballe B, Poole RK. Microbial ubiquinones: multiple roles in respiration, gene regulation and oxidative stress management.Microbiology. 1999 Aug;145 ( Pt 8):1817-30. Review.

7.Hsu AY, Poon WW, Shepherd JA, Myles DC, Clarke CF.Complementation of coq3 mutant yeast by mitochondrial targeting of the Escherichia coli UbiG polypeptide: evidence that UbiG catalyzes both O-methylation steps in ubiquinone biosynthesis. Biochemistry, 1996, Jul 30;35(30):9797-806.

8.Zhang H, Javor GT. "Regulation of the isofunctional genes ubiD and ubiX of the ubiquinone biosynthetic pathway of Escherichia coli." FEMS Microbiol Lett. 2003; 223(1);67-72.

9.Stadthagen G, Kordulakova J, Griffin R, Constant P, Bottova I, Barilone N, Gicquel B, Daffe M, Jackson M. p-Hydroxybenzoic acid synthesis in Mycobacterium tuberculosis.
J Biol Chem. 2005 Dec 9;280(49):40699-706. PMID: 16210318

10.M. Gulmezian, H. Zhang, G. T. Javor, and C. F. Clarke.Genetic Evidence for an Interaction of the UbiG O-Methyltransferase with UbiX in Escherichia coli Coenzyme Q Biosynthesis.
J. Bacteriol., September 1, 2006; 188(17): 6435 - 6439.

11. Liu J, Liu JH. Ubiquinone (coenzyme Q) biosynthesis in Chlamydophila pneumoniae AR39: identification of the ubiD gene.Acta Biochim Biophys Sin (Shanghai). 2006 Oct;38(10):725-30.
PMID: 17033719

12. M. Gulmezian, H. Zhang, G. T. Javor, and C. F. Clarke. Genetic Evidence for an Interaction of the UbiG O-Methyltransferase with UbiX in Escherichia coli Coenzyme Q Biosynthesis.
J. Bacteriol., September 1, 2006; 188(17): 6435 - 6439.

13. A. Johnson, P. Gin, B. N. Marbois, E. J. Hsieh, M. Wu, M. H. Barros, C. F. Clarke, and A. Tzagoloff. COQ9, a New Gene Required for the Biosynthesis of Coenzyme Q in Saccharomyces cerevisiae. J. Biol. Chem., 2005; 280(36): 31397 - 31404.

14. Marbois, B. N., Gin, P., Faull, K. F., Poon, W. W., Lee, P. T., Strahan, J., Shepherd, J. N., and Clarke, C. F. (2005) Coq3 and Coq4 Define a Polypeptide Complex in Yeast Mitochondria for the Biosynthesis of Coenzyme Q. J. Biol. Chem. 280, 20231–20238

15. M. H. Barros, A. Johnson, P. Gin, B. N. Marbois, C. F. Clarke, and A. Tzagoloff. The Saccharomyces cerevisiae COQ10 Gene Encodes a START Domain Protein Required for Function of Coenzyme Q in Respiration. J. Biol. Chem., December 30, 2005; 280(52): 42627 - 42635.




















For more information, please check out the description and the additional notes tabs, below

Literature Referencesp-Hydroxybenzoic acid synthesis in Mycobacterium tuberculosis. Stadthagen G The Journal of biological chemistry 2005 Dec 916210318
Regulation of the ubiquinone (coenzyme Q) biosynthetic genes ubiCA in Escherichia coli. Kwon O Current microbiology 2005 Apr15902464
Ubiquinone (coenzyme Q) biosynthesis in Chlamydophila pneumoniae AR39: identification of the ubiD gene. Liu J Acta biochimica et biophysica Sinica 2006 Oct17033719
DiagramFunctional RolesSubsystem SpreadsheetDescriptionAdditional NotesScenarios 

Genome '1116007.3' is not present in this subsystem.

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