Coenzyme cytochrome

The cytochrome P450 system is the principal enzyme system for the metabolism of lipophilic xenobiotics. It is a heme-containing, membrane-bound, multi-enzyme system which is present in many tissues in vivo but is present at the highest level in liver. A coenzyme, cytochrome P450 NADPH oxidoreductase (OR), is essential for P450 catalytic function and cytochrome bs may stimulate catalytic activities of some enzymes. In human liver, it is estimated that there are 15-20 different xenobiotic-metabolizing cytochrome P450 forms. A standard nomenclature, based on relatedness of the amino acid sequences, has been developed (Nelson et al., 1993). The most recent... 

Cobalt B Enzymes Coenzymes Cytochrome Oxidase Iron Heme Proteins Electron Transport Iron Proteins with Dinuclear Active Sites Iron Proteins with Mononuclear Active Sites Iron-Sulfur Models of Protein Active Sites Metallocenter Biosynthesis Assembly. Metalloregulation Molybdenum MPT-containing Enzymes Nickel Enzymes Cofactors Nitrogenase Catalysis Assembly Photosynthesis Tungsten Proteins Vanadium in Biology Zinc DNA-binding Proteins. 

The protein-functionalization of a decylamine modified MAH-PP supported biomimetic membrane was tested by the incorporation of cytochrome c oxidase (CcOX) from Paracoccus denitriflcans. CcOX is part of the respiratory chain and is responsible for the active transport of protons against the gradient of the electrochemical potential across the lipid membrane. This reaction is driven by the enzymatic reduction of dioxygen where electrons are derived from the coenzyme cytochrome c. This process has been studied using mitochondria or CcOX reconstituted in liposomes and by the incorporation into tethered lipid membranes. 

Two and twelve moles of ATP are produced, respectively, per mole of glucose consumed in the glycolytic pathway and each turn of the Krebs (citrate) cycle. In fat metaboHsm, many high energy bonds are produced per mole of fatty ester oxidized. Eor example, 129 high energy phosphate bonds are produced per mole of palmitate. Oxidative phosphorylation has a remarkable 75% efficiency. Three moles of ATP are utilized per transfer of two electrons, compared to the theoretical four. The process occurs via a series of reactions involving flavoproteins, quinones such as coenzyme Q, and cytochromes. 

In the third complex of the electron transport chain, reduced coenzyme Q (UQHg) passes its electrons to cytochrome c via a unique redox pathway known as the Q cycle. UQ cytochrome c reductase (UQ-cyt c reductase), as this complex is known, involves three different cytochromes and an Fe-S protein. In the cytochromes of these and similar complexes, the iron atom at the center of the porphyrin ring cycles between the reduced Fe (ferrous) and oxidized Fe (ferric) states. 

It should be emphasized here that the four major complexes of the electron transport chain operate quite independently in the inner mitochondrial membrane. Each is a multiprotein aggregate maintained by numerous strong associations between peptides of the complex, but there is no evidence that the complexes associate with one another in the membrane. Measurements of the lateral diffusion rates of the four complexes, of coenzyme Q, and of cytochrome c in the inner mitochondrial membrane show that the rates differ considerably, indicating that these complexes do not move together in the membrane. Kinetic studies with reconstituted systems show that electron transport does not operate by means of connected sets of the four complexes. 

Thenoyltrifluoroacetone and carboxin and its derivatives specifically block Complex II, the succinate-UQ reductase. Antimycin, an antibiotic produced by Streptomyees griseus inhibits the UQ-cytochrome c reductase by blocking electron transfer between bn and coenzyme Q in the Q site. Myxothiazol inhibits the same complex by acting at the site. 

In the endoplasmic reticulum of eukaryotic cells, the oxidation of the terminal carbon of a normal fatty acid—a process termed ch-oxidation—can lead to the synthesis of small amounts of dicarboxylic acids (Figure 24.27). Cytochrome P-450, a monooxygenase enzyme that requires NADPH as a coenzyme and uses O, as a substrate, places a hydroxyl group at the terminal carbon. Subsequent oxidation to a carboxyl group produces a dicarboxylic acid. Either end can form an ester linkage to CoA and be subjected to /3-oxidation, producing a... 

The sulfite reductase from the hyperthermophilic methanogen Methanocaldococcus jannashii is able to reduce the otherwise toxic sulfite to sulfide that is required for growth. In contrast to most organisms that use nicotinamides and cytochromes as electron carriers, this organism uses a coenzyme p42o-dependent reductase (Johnson and Mukhopadhyay 2005). 

A redox reaction is a special case of the equilibrium reaction of A + B in Equation 13.1 B is now a reducible group in a biomolecule with an EPR spectrum either in its oxidized or in its reduced state (or both), and A is now an electron or a pair of electrons, that is, reducing equivalents provided by a natural redox partner (a reductive substrate, a coenzyme such as NADH, a protein partner such as cytochrome c), or by a chemical reductant (dithionite), or even by a solid electrode ... 

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). 

Abnormalities of the respiratoiy chain. These are increasingly identified as the hallmark of mitochondrial diseases or mitochondrial encephalomyopathies [13]. They can be identified on the basis of polarographic studies showing differential impairment in the ability of isolated intact mitochondria to use different substrates. For example, defective respiration with NAD-dependent substrates, such as pyruvate and malate, but normal respiration with FAD-dependent substrates, such as succinate, suggests an isolated defect of complex I (Fig. 42-3). However, defective respiration with both types of substrates in the presence of normal cytochrome c oxidase activity, also termed complex IV, localizes the lesions to complex III (Fig. 42-3). Because frozen muscle is much more commonly available than fresh tissue, electron transport is usually measured through discrete portions of the respiratory chain. Thus, isolated defects of NADH-cytochrome c reductase, or NADH-coenzyme Q (CoQ) reductase suggest a problem within complex I, while a simultaneous defect of NADH and succinate-cytochrome c reductase activities points to a biochemical error in complex III (Fig. 42-3). Isolated defects of complex III can be confirmed by measuring reduced CoQ-cytochrome c reductase activity. 

Porphyrins 21 are the backbone of major players in life cycles—cytochromes (Scheme 8). There are three types of cytochromes, classified by their color, or more precisely by their long-wavelength absorption band, as a (600 mn), b (563 nm), and c (550 nm). They are protein conjugates of a porphyrin complex with iron(II), which is a coenzyme called heme (22). In plants, porphyrins form a complex with magnesium-(II) chlorophylls a and b (23), vital in photosynthesis. Porphyrin derivatives are used in photodynamic therapy for dermatological diseases such as psoriasis, and for skin or subcutaneous cancer.5c-e... 

The first of these new, electron transferring components was coenzyme Q (CoQ). Festenstein in R.A. Morton s laboratory in Liverpool had isolated crude preparations from intestinal mucosa in 1955. Purer material was obtained the next year from rat liver by Morton. The material was lipid soluble, widely distributed, and had the properties of a quinone and so was initially called ubiquinone. Its function was unclear. At the same time Crane, Hatefi and Lester in Wisconsin were trying to identify the substances in the electron transport chain acting between NADH and cytochrome b. Using lipid extractants they isolated a new quininoid coenzyme which showed redox changes in respiration. They called it coenzyme Q (CoQ). CoQ was later shown to be identical to ubiquinone. 

Fischer, V., Johanson, L., Heitz, F., Tullmann, R., Graham, E., Baldeck, J.P. and Robinson, W.T., The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab. Dispos., 1999, 27, 410 16. 

Figure 6.1 Pathways involved in glucose oxidation by plant cells (a) glycolysis, (b) Krebs cycle, (c) mitochondrial cytochrome chain. Under anoxic conditions. Reactions 1, 2 and 3 of glycolysis are catalysed by lactate dehydrogenase, pyruvate decarboxylase and alcohol dehydrogenase, respectively. ATP and ADP, adenosine tri- and diphosphate NAD and NADHa, oxidized and reduced forms of nicotinamide adenine dinucleotide PGA, phosphoglyceraldehyde PEP, phosphoenolpyruvate Acetyl-CoA, acetyl coenzyme A FP, flavoprotein cyt, cytochrome e, electron. (Modified from Fitter and Hay, 2002). Reprinted with permission from Elsevier...

Most compounds oxidized by the electron transport chain donate hydrogen to NAD+, and then NADH is reoxidized in a reaction coupled to reduction of a flavoprotein. During this transformation, sufficient energy is released to enable synthesis of ATP from ADP. The reduced flavoprotein is reoxidized via reduction of coenzyme Q subsequent redox reactions then involve cytochromes and electron transfer processes rather than hydrogen transfer. In two of these cytochrome redox reactions, there is sufficient energy release to allow ATP synthesis. In... 

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