Ubiquinone-10, synthesis

The development status of these molecules is not known. It will be interesting to note whether any differences emerge from the CAAX competitive versus FPP competitive molecules as more data become available for these compounds. Since FPP itself contributes to the CAAX peptide binding pocket, the interaction of FPP competitive FTIs with CAAX peptide competitive FTIs will be of interest. The selectivity of FPP competitive FTIs for the FTase pathway versus other biochemical pathways utilizing FPP, such as ubiquinone synthesis and the heme farnesyltransferase, has also not been reported. These other FPP reactions have important roles in mitochondrial function, which presents some risk for adverse events or possibly opportimities for modulating early apoptotic events. 

The vitamins K and other naphthoquinones arise from O-succinylbenzoate84 86 whose synthesis from chorismate and 2-oxoglutarate depends upon a thiamine diphosphate-bound intermediate, as indicated in Fig. 25-4. Elimination of pyruvate yields O-succinylbenzoate. The remaining reactions of decarboxylation, methylation, and prenylation (Fig. 25-4) resemble those of ubiquinone synthesis. 

Basselin M, Hunt SM, Abdala-Valencia H, Kaneshiro ES. Ubiquinone synthesis in mitochondrial and microsomal subcellular fractions of Pneumocystis spp differential sensitivities to atovaquone. Eukaryot Cell. 2005 4 1483-1492. 

There was no relationship between rate of synthesis or hepatic content of ubiquinone in the rat and the production and excretion of p-hydroxybenzoate.393 Exposure to low temperatures caused an increase in ubiquinone synthesis, whilst starvation or feeding with cholesterol or cholic acid resulted in a reduction of the conversion of p-hydroxybenzaldehyde into ubiquinone no feedback by the end-product seemed to be operative. 

When a P. aeruginosa mutant (PALS 128) was grown under iron rich conditions, the specific activity of the SA-forming enzymes was below the limits of detection [79]. Liu et al. [88], suggest that entC gene expression may be limited at the translational level as well, even when the operon is induced under iron deficiency. This may be understandable because chorismic acid is an essential metabolite for Phe, Trp, Tyr, folate and ubiquinone synthesis. In B. subtilis it was shown that the accumulation of 2,3-DHBA(Glycine) was influenced by the levels of aromatic amino acids and anthranilic acid. Anthranilic acid inhibited the synthesis of DHBA from chorismic acid [117]. It seemed that the reduction in phenolic acid accumulation caused by aromatic amino acids is a consequence of enzyme repression [121]. The synthesis of 2,3-DHBA in B. subtilis is also reduced by other phenolic acids, such as m-substimted benzoic acids. Inhibition of accumulation of phenolic acid by other phenolic acids, would indicate a fairly specific effect on phenolic acid synthesis, but not on the accumulation of coproporphyrin that also accumulates in iron-deficient cultures oiB. subtilis [121]. 

Biochemical and genetic studies in the long-lived Caenorhabditis clk-1 mutants demon-shated that these mutants are Q auxotrophs. CLK-1 is a mitochondrial polypeptide with sequence and functional conservation from human to yeast. Tire Saccharomyces cerevisiae homolog CoqVp is essential for ubiquinone synthesis and thus respuation. Development of the clk-1 mutants requires a dietary source of Coenzyme... 

Another consequence of vitamin A deficiency which may influence gallstone formation is the reduced conversion of squalene to cholesterol, with subsequent diversion of mevalonate to ubiquinone synthesis (176). This effect. 

Genetic and biochemical studies have led to almost complete elucidation of the CoQ8 biosynthesis pathway in E. coli. Homologues of genes involved in this pathway were identified in several other bacterial species, suggesting that ubiquinone synthesis is highly conserved among prokaryotes (Fig. 15.2). 

FIGURE 8.18 Dolichol phosphate is an initiation point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems, undecaprenol, also known as bactoprenol, consists of 11 isoprene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the synthesis of cell wall components such as peptidoglycans, lipopolysaccharides, and glycoproteins. Polyprenyl compounds also serve as the side chains of vitamin K, the ubiquinones, plastoquinones, and tocopherols (such as vitamin E). 

Coenzyme Qio (ubiquinone) is a coenzyme in the mitochondrial respiratoiy chain. It has a side chain made up of 10 isoprene units. Its synthesis can be inhibited by... 

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. 

The reaction has been applied for the synthesis of polyprenyl quinol natural product ubiquinone and vitamin K. 

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

Ubiquinone (also called coenzyme Q) and plasto-quinone (Fig. 10-22d, e) are isoprenoids that function as lipophilic electron carriers in the oxidation-reduction reactions that drive ATP synthesis in mitochondria and chloroplasts, respectively. Both ubiquinone and plasto-quinone can accept either one or two electrons and either one or two protons (see Fig. 19-54). 

FIGURE 19-9 IMADH ubiquinone oxidoreductase (Complex I). Complex I catalyzes the transfer of a hydride ion from NADH to FMN, from which two electrons pass through a series of Fe-S centers to the iron-sulfur protein N-2 in the matrix arm of the complex. Electron transfer from N-2 to ubiquinone on the membrane arm forms QH2, which diffuses into the lipid bilayer. This electron transfer also drives the expulsion from the matrix of four protons per pair of electrons. The detailed mechanism that couples electron and proton transfer in Complex I is not yet known, but probably involves a Q cycle similar to that in Complex III in which QH2 participates twice per electron pair (see Fig. 19-12). Proton flux produces an electrochemical potential across the inner mitochondrial membrane (N side negative, P side positive), which conserves some of the energy released by the electron-transfer reactions. This electrochemical potential drives ATP synthesis. 

FIGURE 19-33 Bacterial respiratory chain, (a) Shown here are the respiratory carriers of the inner membrane of E. coli. Eubacteria contain a minimal form of Complex I, containing all the prosthetic groups normally associated with the mitochondrial complex but only 14 polypeptides. This plasma membrane complex transfers electrons from NADH to ubiquinone or to (b) menaquinone, the bacterial equivalent of ubiquinone, while pumping protons outward and creating an electrochemical potential that drives ATP synthesis. 

In addition to its role as an intermediate in cholesterol biosynthesis, isopentenyl pyrophosphate is the activated precursor of a huge array of biomolecules with diverse biological roles (Fig. 21-48). They include vitamins A, E, and K plant pigments such as carotene and the phytol chain of chlorophyll natural rubber many essential oils (such as the fragrant principles of lemon oil, eucalyptus, and musk) insect juvenile hormone, which controls metamorphosis dolichols, which serve as lipid-soluble carriers in complex polysaccharide synthesis and ubiquinone and plastoquinone, electron carriers in mitochondria and chloroplasts. Collectively, these molecules are called isoprenoids. More than... 

Figure 18-5 A current concept of the electron transport chain of mitochondria. Complexes I, III, and IV pass electrons from NADH or NADPH to 02, one NADH or two electrons reducing one O to HzO. This electron transport is coupled to the transfer of about 12 H+ from the mitochondrial matrix to the intermembrane space. These protons flow back into the matrix through ATP synthase (V), four H+ driving the synthesis of one ATP. Succinate, fatty acyl-CoA molecules, and other substrates are oxidized via complex II and similar complexes that reduce ubiquinone Q, the reduced form QH2 carrying electrons to complex III. In some tissues of some organisms, glycerol phosphate is dehydrogenated by a complex that is accessible from the intermembrane space.

The flavin of NAD dehydrogenase was an obvious candidate for a carrier, as was ubiquinone. However, the third loop presented a problem. Mitchell s solution was the previously discussed Q cycle, which is shown in Fig. 18-9. This accomplishes the pumping in complex III of 2 H+/ e, the equivalent of two loops.111 However, as we have seen, the magnitude of Ap suggests that 4 H+, rather than 2 H+, may be coupled to synthesis of one ATP. If this is true, mitochondria must pump 12 H+/ O rather than six when dehydrogenating NADH, or eight H+/ O when dehydrogenating succinate. 

V). The centers resemble PSII of chloroplasts and have a high midpoint electrode potential E° of 0.46 V. The initial electron acceptor is the Mg2+-free bacteriopheophytin (see Fig. 23-20) whose midpoint potential is -0.7 V. Electrons flow from reduced bacteriopheophytin to menaquinone or ubiquinone or both via a cytochrome bct complex, similar to that of mitochondria, then back to the reaction center P870. This is primarily a cyclic process coupled to ATP synthesis. Needed reducing equivalents can be formed by ATP-driven reverse electron transport involving electrons removed from succinate. Similarly, the purple sulfur bacteria can use electrons from H2S. 

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