Respiratory Ubiquinone

Two groups of substituted l,4-ben2oquiaones are associated with photosynthetic and respiratory pathways the plastoquinones, eg, plastoquinone [4299-57-4] (34), and the ubiquinones, eg, ubiquinone [1339-63-5] (35), are involved in these processes. Although they are found in all living tissue and are central to life itself, a vast amount remains to be learned about their biological roles. 

Walker, J. E., 1992. The NADH ubiquinone oxidoreducta.se (Complex I) of respiratory chains. Quarterly Reviews of Biophysics 25 253-324. 

Atovaquone, a hydroxynaphthoquinone, selectively inhibits the respiratory chain of protozoan mitochondria at the cytochrome bcl complex (complex III) by mimicking the natural substrate, ubiquinone. Inhibition of cytochrome bcl disrupts the mitochondrial electron transfer chain and leads to a breakdown of the mitochondrial membrane potential. Atovaquone is effective against all parasite stages in humans, including the liver stages. 

Another pathway is the L-glycerol 3-phosphate shuttle (Figure 11). Cytosolic dihydroxyacetone phosphate is reduced by NADFl to s.n-glycerol 3-phosphate, catalyzed by s,n-glycerol 3-phosphate dehydrogenase, and this is then oxidized by s,n-glycerol 3-phosphate ubiquinone oxidoreductase to dihydroxyacetone phosphate, which is a flavoprotein on the outer surface of the inner membrane. By this route electrons enter the respiratory chain.from cytosolic NADH at the level of complex III. Less well defined is the possibility that cytosolic NADH is oxidized by cytochrome bs reductase in the outer mitochondrial membrane and that electrons are transferred via cytochrome b5 in the endoplasmic reticulum to the respiratory chain at the level of cytochrome c (Fischer et al., 1985). 

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

This complex consists of four subunits, all of which are encoded on nuclear DNA, synthesized on cytosolic ribosomes, and transported into mitochondria. The succinate dehydrogenase (SDH) component of the complex oxidizes succinate to fumarate with transfer of electrons via its prosthetic group, FAD, to ubiquinone. It is unique in that it participates both in the respiratory chain and in the tricarboxylic acid (TC A) cycle. Defects of complex II are rare and only about 10 cases have been reported to date. Clinical syndromes include myopathy, but the major presenting features are often encephalopathy, with seizures and psychomotor retardation. Succinate oxidation is severely impaired (Figure 11). 

Ubiquinone or Q (coenjyme Q) (Figure 12-5) finks the flavoproteins to cytochrome h, the member of the cytochrome chain of lowest redox potential. Q exists in the oxidized quinone or reduced quinol form under aerobic or anaerobic conditions, respectively. The structure of Q is very similar to that of vitamin K and vitamin E (Chapter 45) and of plastoquinone, found in chloroplasts. Q acts as a mobile component of the respiratory chain that collects reducing equivalents from the more fixed flavoprotein complexes and passes them on to the cytochromes. 

Figure 12-7. Proposed sites of inhibition (0) of the respiratory chain by specific drugs, chemicals, and antibiotics. The sites that appear to support phosphorylation are indicated. BAL, dimercaprol. TTFA, an Fe-chelating agent. Complex I, NADHiubiquinone oxidoreductase complex II, succinate ubiquinone oxidoreductase complex III, ubiquinohferricytochrome c oxidoreductase complex IV, ferrocytochrome ctoxygen oxidoreductase. Other abbreviations as in Figure 12-4.

Figure 12-8. Principles of the chemiosmotic theory of oxidative phosphorylation. The main proton circuit is created by the coupling of oxidation in the respiratory chain to proton translocation from the inside to the outside of the membrane, driven by the respiratory chain complexes I, III, and IV, each of which acts as a protonpump. Q, ubiquinone C, cytochrome c F Fq, protein subunits which utilize energy from the proton gradient to promote phosphorylation. Uncoupling agents such as dinitrophenol allow leakage of H" across the membrane, thus collapsing the electrochemical proton gradient. Oligomycin specifically blocks conduction of H" through Fq.

Although not steroids, these compounds are related because they are synthesized, like cholesterol (Figure 26-2), from five-carbon isoprene units (Figure 14-19). They include ubiquinone (Chapter 12), a member of the respiratory chain in mitochondria, and the long-... 

Ubiquinone, known also as coenzyme Q, plays a crucial role as a respiratory chain electron carrier transport in inner mitochondrial membranes. It exerts this function through its reversible reduction to semiquinone or to fully hydrogenated ubiquinol, accepting two protons and two electrons. Because it is a small lipophilic molecule, it is freely diffusable within the inner mitochondrial membrane. Ubiquinones also act as important lipophilic endogenous antioxidants and have other functions of great importance for cellular metabolism. ... 

Now, we may consider in detail the mechanism of oxygen radical production by mitochondria. There are definite thermodynamic conditions, which regulate one-electron transfer from the electron carriers of mitochondrial respiratory chain to dioxygen these components must have the one-electron reduction potentials more negative than that of dioxygen Eq( 02 /02]) = —0.16 V. As the reduction potentials of components of respiratory chain are changed from 0.320 to +0.380 V, it is obvious that various sources of superoxide production may exist in mitochondria. As already noted earlier, the two main sources of superoxide are present in Complexes I and III of the respiratory chain in both of them, the role of ubiquinone seems to be dominant. Although superoxide may be formed by the one-electron oxidation of ubisemiquinone radical anion (Reaction (1)) [10,22] or even neutral semiquinone radical [9], the efficiency of these ways of superoxide formation in mitochondria is doubtful. 

Ubiquinones (coenzymes Q) Q9 and Qi0 are essential cofactors (electron carriers) in the mitochondrial electron transport chain. They play a key role shuttling electrons from NADH and succinate dehydrogenases to the cytochrome b-c1 complex in the inner mitochondrial membrane. Ubiquinones are lipid-soluble compounds containing a redox active quinoid ring and a tail of 50 (Qio) or 45 (Q9) carbon atoms (Figure 29.10). The predominant ubiquinone in humans is Qio while in rodents it is Q9. Ubiquinones are especially abundant in the mitochondrial respiratory chain where their concentration is about 100 times higher than that of other electron carriers. Ubihydroquinone Q10 is also found in LDL where it supposedly exhibits the antioxidant activity (see Chapter 23). 

There are two kinds of redox interactions, in which ubiquinones can manifest their antioxidant activity the reactions with quinone and hydroquinone forms. It is assumed that the ubiquinone-ubisemiquinone pair (Figure 29.10) is an electron carrier in mitochondrial respiratory chain. There are numerous studies [235] suggesting that superoxide is formed during the one-electron oxidation of ubisemiquinones (Reaction (25)). As this reaction is a reversible one, its direction depends on one-electron reduction potentials of semiquinone and dioxygen. 

Mitchell, P. (1975) Protonmotive redox mechanism of the cytochrome b-c1 complex in the respiratory chain protonmotive ubiquinone cycle, FEBS Lett., 56, 1-6. 

A naturally occurring phenazine of nonbacterial origin is the methano-phenazine (MP) (10) which has been isolated from the cytoplasmic membrane of Methanosarcina (Ms.) mazei Gol archaea. The structure, synthesis, properties, and function of this natural product will be discussed in detail since it is not only the first and so far the sole phenazine derivative from archaea, but also the first one that is acting as an electron carrier in a respiratory chain - a biologic function equivalent to that of ubiquinones in mitochondria and bacteria. 

In the hydrogenosomal membranes, EPR spectra showed no trace of the highly characteristic features of the iron-sulfur clusters of complex I (NADH ubiquinone reductase) and the Rieske protein of complex III of the mitochondrial respiratory chain. This is consistent with the absence of... 

Cytochrome bci is a multicomponent enzyme found in the inner mitochron-drial membrane of eukaryotes and in the plasma membrane of bacteria. The cytochrome bci complex functions as the middle component of the mitochondrial respiratory chain, coupling electron transfer between ubiquinone/ ubiquinol (see Figure 7.27) and cytochrome c. 

The role of ubiquinone (coenzyme Q, 4) in transferring reducing equivalents in the respiratory chain is discussed on p. 140. During reduction, the quinone is converted into the hydroquinone (ubiquinol). The isoprenoid side chain of ubiquinone can have various lengths. It holds the molecule in the membrane, where it is freely mobile. Similar coenzymes are also found in photosynthesis (plastoquinone see p. 132). Vitamins E and K (see p. 52) also belong to the quinone/hydroquinone systems. 

The tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) is a cyclic metabolic pathway in the mitochondrial matrix (see p. 210). in eight steps, it oxidizes acetyl residues (CH3-CO-) to carbon dioxide (CO2). The reducing equivalents obtained in this process are transferred to NAD"" or ubiquinone, and from there to the respiratory chain (see p. 140). Additional metabolic functions of the cycle are discussed on p. 138. 

The respiratory chain is one of the pathways involved in oxidative phosphorylation (see p. 122). It catalyzes the steps by which electrons are transported from NADH+H or reduced ubiquinone (QH2) to molecular oxygen. Due to the wide difference between the redox potentials of the donor (NADH+H or QH2) and the acceptor (O2), this reaction is strongly exergonic (see p. 18). Most of the energy released is used to establish a proton gradient across the inner mitochondrial membrane (see p. 126), which is then ultimately used to synthesize ATP with the help of ATP synthase. 

Electrons enter the respiratory chain in various different ways. In the oxidation of NADH+H" by complex I, electrons pass via FMN and Fe/S clusters to ubiquinone (Q). Electrons arising during the oxidation of succinate, acyl CoA, and other substrates are passed to ubiquinone by succinate dehydrogenase or other mitochondrial dehydrogenases via en-... 

Fig.3.8.3 Oxygen uptake by intact (a) and digitonin-permeabilized (b) fibroblasts. I-V Respiratory chain complexes I-V, AcCoA acetylcoenzyme A, BSA bovine serum albumin, CCP carbonyl cyanide m-chlorophenylhydrazone, Cit citrate, CoA coenzyme A, CS citrate synthase, Dig digitonin, Fo FI the ATPase components, Fum fumarase, G3P glycerol-3-phosphate, im inner membrane, Mai malate, Malo malonate, MDH malate dehydrogenase, OAA oxaloacetate, om outer membrane, PDH pyruvate dehydrogenase, Pi inorganic phosphate, Pyr pyruvate, Q ubiquinone, Rot rotenone, Succ succinate, t time...

Ubiquinone (mitochondrial respiratory chain, anti-oxidant)... 

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