Oxidative phosphorylation synthesis

I 13 Fungicides Acting on Oxidative Phosphorylation Synthesis of azoxystrobin... 

Mitochondria organize electron transfer and the associated reactions leading to the adenosine triphosphate synthesis called oxidative phosphorylation. Synthesis of adenosine triphosphate is an endothermic reaction, and hence conserves the energy released during biological oxidation-reduction reactions. Electron transfer and associated reactions leading to ATP synthesis are membrane-bound phenomena. NADH and FADH2 are the reduced cofactors of NAD" " and the FAD. The oxidation of one NADH produces approximately three... 

Although the interior of a prokaryotic cell is not subdivided into compartments by internal membranes, the cell still shows some segregation of metabolism. For example, certain metabolic pathways, such as phospholipid synthesis and oxidative phosphorylation, are localized in the plasma membrane. Also, protein biosynthesis is carried out on ribosomes. 

Glycolysis and the citric acid cycle (to be discussed in Chapter 20) are coupled via phosphofructokinase, because citrate, an intermediate in the citric acid cycle, is an allosteric inhibitor of phosphofructokinase. When the citric acid cycle reaches saturation, glycolysis (which feeds the citric acid cycle under aerobic conditions) slows down. The citric acid cycle directs electrons into the electron transport chain (for the purpose of ATP synthesis in oxidative phosphorylation) and also provides precursor molecules for biosynthetic pathways. Inhibition of glycolysis by citrate ensures that glucose will not be committed to these activities if the citric acid cycle is already saturated. 

FIGURE 20.1 Pyruvate produced hi glycolysis is oxidized in the tricarboxylic acid (TCA) cycle. Electrons liberated in this oxidation flow through the electron transport chain and drive the synthesis of ATP in oxidative phosphorylation. In eukaryotic cells, this overall process occurs in mitochondria. 

Wall Piece IV (1985), a kinetic sculpture by George Rhoads. This complex meehanieal art form can be viewed as a metaphor for the molecular apparatus underlying electron transport and ATP synthesis by oxidative phosphorylation. (1985 ty George Rhoaeh)... 

Whereas ATP made in glycolysis and the TCA cycle is the result of substrate-level phosphorylation, NADH-dependent ATP synthesis is the result of oxidative phosphorylation. Electrons stored in the form of the reduced coenzymes, NADH or [FADHa], are passed through an elaborate and highly orga-... 

Because the 2 NADH formed in glycolysis are transported by the glycerol phosphate shuttle in this case, they each yield only 1.5 ATP, as already described. On the other hand, if these 2 NADH take part in the malate-aspartate shuttle, each yields 2.5 ATP, giving a total (in this case) of 32 ATP formed per glucose oxidized. Most of the ATP—26 out of 30 or 28 out of 32—is produced by oxidative phosphorylation only 4 ATP molecules result from direct synthesis during glycolysis and the TCA cycle. 

Under these conditions, what is the maximum ratio of [ATP]/[ADP] attainable by oxidative phosphorylation when [PJ = 1 mM (Assume AG° for ATP synthesis = +30.5 kj/mol.)... 

Many inhibitors of substrate oxidations, substrate transport, electron transport, and ATP synthesis are known including many well-known toxins (see Sherratt, 1981 Harold, 1986 Nicholls and Ferguson, 1992). These are not discussed here except to mention specific uncouplers of oxidative phosphorylation. Classic uncouplers such as 2,4-dinitrophenol have protonated and unprotonated forms, both of which are lipid soluble and cross the inner mitochondrial membrane discharging the proton gradient. This prevents ATP synthesis and stimulates respiration. 

Vance, J.E., eds.), pp. 116-142, Benjamin/Cummings Publishing Co., Menlo Park, California. Senior, A.E. (1988). ATP synthesis by oxidative phosphorylation. Physiological Rev. 68, 177-230. Senior, A.E. (1990). The proton-translocating ATPase of Esherichia colt. Ann. Rev. Biophys. Chem. 19,7- 1. 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Mechanistic studies have shown that TBT and certain other forms of trialkyltin have two distinct modes of toxic action in vertebrates. On the one hand they act as inhibitors of oxidative phosphorylation in mitochondria (Aldridge and Street 1964). Inhibition is associated with repression of ATP synthesis, disturbance of ion transport across the mitochondrial membrane, and swelling of the membrane. Oxidative phosphorylation is a vital process in animals and plants, and so trialkyltin compounds act as wide-ranging biocides. Another mode of action involves the inhibition of forms of cytochrome P450, which was referred to earlier in connection with metabolism. This has been demonstrated in mammals, aquatic invertebrates and fish (Morcillo et al. 2004, Oberdorster 2002). TBTO has been shown to inhibit P450 activity in cells from various tissues of mammals, including liver, kidney, and small intestine mucosa, both in vivo and in vitro (Rosenberg and Drummond 1983, Environmental Health Criteria 116). 

Figure 12-14. The creatine phosphate shuttle of heart and skeletal muscle. The shuttle allows rapid transport of high-energy phosphate from the mitochondrial matrix into the cytosol. CKg, creatine kinase concerned with large requirements for ATP, eg, muscular contraction CIC, creatine kinase for maintaining equilibrium between creatine and creatine phosphate and ATP/ADP CKg, creatine kinase coupling glycolysis to creatine phosphate synthesis CK, , mitochondrial creatine kinase mediating creatine phosphate production from ATP formed in oxidative phosphorylation P, pore protein in outer mitochondrial membrane.

Pathways are compartmentalized within the cell. Glycolysis, glycogenesis, glycogenolysis, the pentose phosphate pathway, and fipogenesis occur in the cytosol. The mitochondrion contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and of oxidative phosphorylation. The endoplasmic reticulum also contains the enzymes for many other processes, including protein synthesis, glycerofipid formation, and dmg metabolism. 

This potential, or protonmotive force as it is also called, in turn drives a number of energy-requiring functions which include the synthesis of ATP, the coupling of oxidative processes to phosphorylation, a metabohc sequence called oxidative phosphorylation and the transport and concentration in the cell of metabolites such as sugars and amino acids. This, in a few simple words, is the basis of the chemiosmotic theory linking metabolism to energy-requiring processes. 

A dynamic model has been proposed for the synthesis of ATP during oxidative phosphorylation in which ADP and inorganic phosphate combine directly to give a quinquecovalent intermediate. While such a model may be valuable in drawing attention to the possible participation of quinquecovalent intermediates in ATP synthesis, no mention is made of the role of oxidation in this reaction. 

A remarkable feature of the bioenergetic oxidation reactions of nutrients in cells is the fact that they are always coupled to another reaction, that of synthesis of the energy-rich chemical substance adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (oxidative phosphorylation Engelgardt and Ljubimova, 1939) ... 

The individual steps of the multistep chemical reduction of COj with the aid of NADPHj require an energy supply. This supply is secured by participation of ATP molecules in these steps. The chloroplasts of plants contain few mitochondria. Hence, the ATP molecules are formed in plants not by oxidative phosphorylation of ADP but by a phosphorylation reaction coupled with the individual steps of the photosynthesis reaction, particularly with the steps in the transition from PSII to PSI. The mechanism of ATP synthesis evidently is similar to the electrochemical mechanism involved in their formation by oxidative phosphorylation owing to concentration gradients of the hydrogen ions between the two sides of internal chloroplast membranes, a certain membrane potential develops on account of which the ATP can be synthesized from ADP. Three molecules of ATP are involved in the reaction per molecule of COj. 

Dinitrophenol is a member of the aromatic family of pesticides, many of which exhibit insecticide and fungicide activity. DNP is considered to be highly toxic to humans, with a lethal oral dose of 14 to 43mg/kg. Environmental exposure to DNP occurs primarily from pesticide runoff to water. DNP is used as a pesticide, wood preservative, and in the manufacture of dyes. DNP is an uncoupler, or has the ability to separate the flow of electrons and the pumping of ions for ATP synthesis. This means that the energy from electron transfer cannot be used for ATP synthesis [75,77]. The mechanism of action of DNP is believed to inhibit the formation of ATP by uncoupling oxidative phosphorylation. 

Synthesis of Phosphonic and Phosphinlc Acids and their Derivatives.-The phosphonium adducts from PCl and alkyl vinyl ethers are converted into the corresponding phosphonic dichlorides by hexamethyldisiloxane. Oxidative phosphorylation of the 1,3-butadienes (53) affords the phosphonic dichlorides (54). 

This can be used in several ways. H+-ATPase plays a key role in oxidative phosphorylation (ATP synthesis) as it transfers protons back into the matrix space with simultaneous synthesis of ATP (with temporary enzyme phosphorylation, cf. page 451). 

Not all the cellular DNA is in the nucleus some is found in the mitochondria. In addition, mitochondria contain RNA as well as several enzymes used for protein synthesis. Interestingly, mitochond-rial RNA and DNA bear a closer resemblance to the nucleic acid of bacterial cells than they do to animal cells. For example, the rather small DNA molecule of the mitochondrion is circular and does not form nucleosomes. Its information is contained in approximately 16,500 nucleotides that func-tion in the synthesis of two ribosomal and 22 transfer RNAs (tRNAs). In addition, mitochondrial DNA codes for the synthesis of 13 proteins, all components of the respiratory chain and the oxidative phosphorylation system. Still, mitochondrial DNA does not contain sufficient information for the synthesis of all mitochondrial proteins most are coded by nuclear genes. Most mitochondrial proteins are synthesized in the cytosol from nuclear-derived messenger RNAs (mRNAs) and then transported into the mito-chondria, where they contribute to both the structural and the functional elements of this organelle. Because mitochondria are inherited cytoplasmically, an individual does not necessarily receive mitochondrial nucleic acid equally from each parent. In fact, mito-chondria are inherited maternally. 

Thus, in one cycle, eight hydrogen atoms (H+ + e ) are transferred to hydrogen-transmitting coenzymes and later oxidized to water in the respiratory chain. This process is linked to oxidative phosphorylation, i.e., the synthesis of ATP from ADP and inorganic phosphate. 

The value of these molecules in synthesis and energy capture, photosynthesis and oxidative phosphorylation, together makes the production of organic molecules, which are energy traps, more rapid and hence the total biomass survival is increased. Overall energy retention is also increased. The particular value of Mg2+ in chlorin is described in Section 5.7. 

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