NEBRASKA REDOX BIOLOGY CENTER EDUCATIONAL PORTAL

Nebraska Redox Biology Center Educational Portal


Ubiquinol/Ubiquinone or Coenzyme Q10

Coenzyme Q10 is a redox active lipid-soluble compound which is synthesized by animals, plants and bacteria. Coenzyme Q10 is present in most cellular membranes. The major form of coenzyme Q10 in human and in most of mammals has 10 isoprene units in the side chain. Such polyisoprenoid side-chain is responsable for anchoring to the molecule to lipid-rich structures. Q10 is an essential carrier for the electron transfer in the mitochondrial respiratory chain for ATP production, and also it acts as an important antioxidant in the body. [ 1, 2, 3, 4 ]. Q10 exists in the oxidized (UQ, ubiquinone), partially reduced (ubisemiquinone radical, UQ.-) and in the reduced form (ubiquinol, UQH2). Coenzyme Q10 undergo reversible redox cycling between the three states. Such redox cycling define coenzyme Q10 its function as electron carrier in the mitochondrial respiratory chain. Coenzyme Q10 transfers electrons from complexes I and II to complex III [ 1, 5, 6 ]. The reduced form (ubiquinol) is a major form of coenzyme Q10 in the cell. Coenzyme Q10 is acting through formation of its semiquinone radical is a major source of cellular and mitochondrial superoxide radical [ 5, 6, 7 ].

Coenzyme Q10. Ubiquinol/Ubiquinone and semiquinone radical [ 8, ].


Coenzyme Q10 has very low toxisity is used as dietary supplement for more than 30 years. Rre-clinical and clinical trails shown that coenzyme Q10 does not cause serious adverse effects in humans. Futhermore, studies on animals and humans suggest that dietary coenzyme Q10 supplementation does not influence biosynthesis of coenzyme Q10 in the cell and does not resulting in accumulation in plasma or tissues. The maximum tolerated doses of coenzyme Q10 were estimated to be in range 250 mg/kg - >4,000 mg/kg for mice and rats. The lethal dose for coenzyme Q10 was greater than 5000 mg/kg for male and female rats [ 9, 10, 11 ].

Respiratory chain electrons flow from NADH to flavin mononucleotide in complex I and are then transferred to the set of Fe-S clusters. The terminal Fe-S cluster interacts with ubisemiquinone radical and, therefore, is thought to be the electron donor to ubiqinone. Transfer of the first electron results in the transient formation of ubisemiquinone radical, and transfer of the second electron reduces the ubisemiquinone radical to the fully reduced UQH2. In this reaction ubisemiquinone radical can react with oxygen to form superoxide [ 1, 12, 13 ]. Reverse electron transport is based electron flow from succinate through complex II to ubiqinone and then to complex I, which finally reduces matrix NAD+ [ 1, 13, 14 ]. Q-cycle is a chain of processes where electrons flow from UQH2 to cytochrome c at complex III. UQH2 binds to the Q(o) site and transfers the first electron to the Rieske iron-sulfur protein (RISP) forming unstable ubisemiquinone radical. This radical donates the second electron to the low-potential heme (bL) of cytochrome b and is then conveyed to the high-potential heme (bH) near the 'in' side (the matrix side) of the membrane. Electron from bH passes to a ubiqinone at the second ubiqinone-binding site, Q(i) resulting in formation of a stable ubisemiquinone radical. At second part of Q-cycle one additional UQH2 molecule is oxidized as described above. Final result of Q cycle is oxidation of two UQH2 and generation of one UQH2 at the Q(i) site, reduction of two cytochrome c molecules, and depositing of four protons into the intermembrane space [ 1, 15 ].

Functions of Ubiquinone (UQ) in the Mitochondrial Respiratory Chain (RC). In normal forward electron transfer, UQ accepts electrons from complexes I and II and passes them singly to complex III. At complex III, the 'Q cycle', which allows pumping of protons from the matrix into the intermembrane space, involves two distinct UQ-binding sites. UQH2 is reduced at the Q(o) site, passing one electron to cytochrome c (cyt c) and the other down to the Qi site, where the electron is given to a bound UQ during the first cycle, forming UQ.-, or to a bound UQ.- generated during the first cycle. Oxidized UQ formed at the Q(o) site and UQH2 formed at the Q(i) site after completion of the 'Q cycle' are free to diffuse out into the UQ pool. As electrons are transported, they may leak to oxygen, forming superoxide (O2.-). Red stars indicate potential sources of O2.- production. Superoxide dismutase (SOD) converts O2.- to hydrogen peroxide (H2O2) that is reduced to water by glutathione peroxidase (GPX). Both O2.- and H2O2 have been implied in modulating the function of signal transduction pathways ('other reactions' in the figure). UQ also accepts electrons from several non-RC dehydrogenases, including the mitochondrial glycerol-3-phosphate dehydrogenase (G3PDH), dihydroorotate dehydrogenase (DHODH), and electron transfer flavoprotein oxidoreductase (ETFQOQ) (see main text for other dehydrogenases not shown in the figure). Uphill electron transfer from UQH2 to NAD+ through complex I is known as reverse electron transport. The I-III-IV supercomplex, which is the most active supramolecular form, is schematically shown on the left of the figure. [ 1, ].

The reduced form of coenzyme Q10 (UQH2) is an effective antioxidant and and inhybitor od lipid peroxidation. Antioxidant properties of coenzyme Q10 are based on reversible redox cycling between the three states:

UQH2 → UQ.- → UQ ;

The primary role of coenzyme Q10 is the prevention of lipid peroxyl radicals (LOO.-) production during initiation. UQH2 reduces the initiating perferryl radical with the formation of ubisemiquinone radical and H2O2. Direct reaction of UQH2 eliminates LOO.- is possible [ 16, 17, 18, 19 ].

Sites of action of ubiquinone on lipid peroxidation. LH - polyunsaturated fatty acid; OH. - hydroxyl radical; Fe3+-O2.- - perferryl radical; CoQH2 - reduced coenzyme Q; CoQH.- - ubisemiquinone radical, L. - carbon-centered radical; LOO. - lipid peroxyl radical; LOOH - lipid hydroperoxide; VitE. - α-tocopheroxyl radical; Asc. - ascorbyl radical [ 16, ].

In addition, the role of coenzyme Q10 in defending proteins from oxidation has been proposed [ 20 ].

Cytosolic NADPH-dependent reductase, lipoamide dehydrogenase DT-diaphorase, glutathione reductase and thioredoxin reductase (TrxR1) are able to reduce oxidized form of coenzyme Q10. Thioredoxin reductase is shown as most effective reductant of coenzyme Q10 [ 21, 22, 23, 24 ].

Coenzyme Q10 biosynthesis is complex process and current knowledge derives mainly from the characterization of coenzyme Q10 intermediates in coenzyme Q10 defficient bacterial and yeast mutant strains. Yeast Saccharomyces cerevisiae coenzyme Q10 biosynthesis involve the products of at least nine genes designated Coq1 to Coq9 [ 25, 26, 27, 28, 29 ].

Schematic illustration of the ubiquinone (UQ) biosynthetic pathway in the yeast Saccharomyces cerevisiae. Ubiquinone biosynthesi in Saccharomyces cerevisiae pathway starts with assembly and elongation of the isoprenoid tail catalyzed by the enzyme Coq1p. Coq2p mediates the condensation of the isoprenoid tail with either one of two basic ring structures, para-hydroxybenzoate (4-HB) or para-aminobenzoate (pABA), producing 3-hexaprenyl-4-hydroxybenzoate (HHB) and 3-hexaprenyl-4-aminobenzoic acid (HAB) respectively. The basic ring moiety then undergoes a series of modifications to produce UQ. NH2-to-OH conversion is thought to takes place prior to demethoxyubiquinone (DMQ6) formation. Enzymes required for 5 of the 7 modifications are shown in blue. A question mark (?) indicates that the protein catalyzing the reaction has yet to be identified. The intermediates that have been detected in yeast coq mutants are shown in brackets. Asterisks indicate compounds that are the main intermediates detected when either 4-HB or pABA are provided as ring precursors. Coq8p is a putative kinase, believed to have a regulatory role in UQ6 biosynthesis. NH2 from pABA and C4-aminated intermediates are shown in red. [ 27, ].


Ubiquinone biosynthesis is highly conserved among prokaryotes. Biosynthesis of E. coli Coenzyme Q8 requires nine ubi genes. Most of them are encoding enzymes that modifying the aromatic ring of the 4-hydroxybenzoate universal precursor [ 25, 26, 30, 31 ].

Biosynthetic pathway of ubiquinone in Escherichia coli. The numbering of the aromatic carbon atoms is shown on coenzyme Q8, and the octaprenyl tail is represented by R on C-3 of the different biosynthetic intermediates. The name of the enzymes catalyzing the reactions (each labeled with a lowercase letter) is indicated. Abbreviations used for 4-hydroxybenzoate (4-HB), 3-octaprenyl-4-hydroxybenzoate (OHB), 3-octaprenylphenol (OPP), coenzyme Q8 (Q8), C1-demethyl-C6-demethoxy-Q8 (DDMQ8), and C6-demethoxy-Q8 (DMQ8) are underlined. The XanB2 protein, present in some prokaryotes but not in E. coli, catalyzes the production of 4-HB from chorismate. [ 31, ].


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