Electron-transport chain inhibition

This type of effect can occur in all tissues and is caused by a metabolic inhibitor such as azide or cyanide, which inhibits the electron transport chain. Inhibition of one or more of the enzymes of the tricarboxylic acid cycle such as that caused by fluoroacetate (Fig. 6.7) also results in inhibition of cellular respiration (for more details of cyanide and fluoroacetate see chap. 7). 

These inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain. Inhibiting respiration prevents the... 

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. 

Although only two protons are pumped out of the matrix, two others from the matrix are consumed in the formation of H2O. There is therefore a net translocation of four positive charges out of the matrix which is equivalent to the extrusion of four protons. If four protons are required by the chemiosmotic mechanism to convert cytosolic ADP + Pj to ATP, then 0.5 mol ATP is made for the oxidation of one mol of ubiquinol and one mol ATP for the oxidation of 2 mols of reduced cytochrome c. These stoichiometries were obtained experimentally when ubiquinol was oxidized when complexes I, II, and IV were inhibited by rotenone, malonate, and cyanide, respectively, and when reduced cytochrome c was oxidized with complex III inhibited by antimycin (Hinkle et al., 1991). (In these experiments, of course, no protons were liberated in the matrix by substrate oxidation.) However, in the scheme illustrated in Figure 6, with the flow of two electrons through the complete electron transport chain from substrate to oxygen, it also appears valid to say that four protons are extmded by complex I, four by complex III, and two by complex 1. 

Figure 11-5. Electron transport chain in microsomes. Cyanide (CN ) inhibits the indicated step.

Hexachlorophane inhibits the electron transport chain in bacteria and thus will inhibit all metabohc activities in aerobic bacteria. 

Hydrogen sulfide inhibits mitochondrial cytochrome oxidase, resulting in disruption of the electron transport chain and impairing oxidative metabolism. Nervous and cardiac tissues, which have the highest oxygen demand (e.g., brain and heart), are especially sensitive to disruption of oxidative metabolism (Ammann 1986 Hall 1996). 

Rotenone inhibits the transfer of electrons from NADH into the electron transport chain. The oxidation of substrates that generate NADH is, therefore, blocked. However, substrates that are oxidized to generate FADH2 (such as succinate or a-glycerol phosphate) can still be oxidized and still generate ATP. Because NADH oxidation is blocked, the NADH pool becomes more reduced in the presence of rotenone since there s nowhere to transfer the electrons. 

Reviewing the criteria for inclusion of components into the electron transport chain, Slater (1958) highlighted considerations previously advanced by H.A. Krebs as necessary to establish a pathway, namely that the amounts of enzyme present must be commensurate with enzymic activity in the preparation, activity should be fully restored by the reintroduction of the postulated component into an inhibited or depleted preparation, and that the rates of oxidation and reduction of components must be at least as great as those in the system overall. Reduction of cytochrome b by the systems then in use was thought by Chance (1952) and Slater (1958) to be too slow for the inclusion of this cytochrome into the main chain. 

FIGURE 11.14 Cyanogenic glycosides inhibit the electron transport chain. 

The electron transport chain is vital to aerobic organisms. Interference with its action may be life threatening. Thus, cyanide and carbon monoxide bind to haem groups and inhibit the action of the enzyme cytochrome c oxidase, a protein complex that is effectively responsible for the terminal part of the electron transport sequence and the reduction of oxygen to water. 

Selected entries from Methods in Enzymology [vol, page(s)] Electron-transport chain [components, 69, 205, 206 sites of inhibition, 69, 676, 677] chloroplast [autoxidizable carriers, 69, 416, 417 DBMIB, 69, 422, 423 dichlorophenolindophenol and related carriers, 69, 418 ferricyanide, 69, 417, 418 isolated, 69,... 

Treatment of isolated hepatocytes with authentic nitric oxide inhibits the electron transport chain at complexes I and II, and mitochondrial aconitase activity (Stadler et al., 1991). 

NO also has cytotoxic effects when synthesized in large quantities, eg, by activated macrophages. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of the heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 

Recently introduced insecticide/acaricides, pyrimidifen and fenaza-quin (Figure 3.13), also inhibit the mitochondrial electron transport chain by binding with complex I at coenzyme site Q. 

Oxidative Phosphorylation. Oxidative phosphorylation, that is the production of ATP during the passage of electrons down the terminal electron transport chain, may be disrupted in two distinct ways. Compounds that divorce the process of electron transport and the phosphorylation of ADP are termed uncoupling agents. They permit NADH and succinate to be oxidised via the electron transport chain without the production of ATP and are lethal. Oxidative phosphorylation may also be inhibited directly, thus preventing the oxidation of NADH and succinate. Several products are available that exploit these modes of action. Characteristically, they have wide activity spectra that span major disciplines of pesticide use. 

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