Enzyme succinate dehydrogenase

The enzyme succinate dehydrogenase (SDH) is competitively inhibited by malo-nate. Figure 14.14 shows the structures of succinate and malonate. The structural similarity between them is obvious and is the basis of malonate s ability to mimic succinate and bind at the active site of SDH. However, unlike succinate, which is oxidized by SDH to form fumarate, malonate cannot lose two hydrogens consequently, it is unreactive. 

As described elsewhere in this chapter, alterations in the activity of a number of lung enzymes have been described after acute and chronic ozone exposure. With the possible exceptions of the sulfhydryl-containing enzyme succinic dehydrogenase and the cytochrome P-4 en me benzopyrene hydroxylase, it is difficult to determine whether these findings are due to a direct oxidative effect of ozone or are secondary to changes in protein synthesis, concentrations of intermediates, or destruction of cells or organelles. 

Answer The flavin nucleotides, FMN and FAD, would not be synthesized. Because FAD is required by the citric acid cycle enzyme succinate dehydrogenase, flavin deficiency would strongly inhibit the cycle. 

The enzyme succinate dehydrogenase (Chaps. 12 and 14) catalyzes the reaction ... 

During subcellular fractionation, various markers can be used as a quality control measure, giving an assessment of the quality of separation of individual fractions for example, DNA can be used as a marker for the step sedimenting nuclei, while the enzyme succinate dehydrogenase can be used as a marker for the step sedimenting mitochondria. Of course, to obtain a pure organelle fraction from differential centrifugation is virtually impossible. 

Ubiquinone functions as a carrier in the mitochondrial electron transport chain it is responsible for the proton pumping associated with complex I (Brandt, 1999) and is directly reduced by the citric acid cycle enzyme succinate dehydrogenase (Lancaster, 2002). As shown in Figure 14.8, it undergoes two single-electron reduction reactions to form the relatively stable semiquinone radical, then the fully reduced quinol. In addition to its role in the electron transport chain, it has been implicated as a coantioxidant in membranes and plasma lipoproteins, acting together with vitamin E (Section 4.3.1 Thomas etal., 1995, 1999). 

Succinate is next dehydrogenated by FAD and the enzyme succinate dehydrogenase to give fumarate, a process analc ous to that of step I in the fatty acid jSI OXidation pathway,... 

The electron carriers in the respiratory assembly of the inner mitochondrial membrane are quinones, flavins, iron-sulfur complexes, heme groups of cytochromes, and copper ions. Electrons from NADH are transferred to the FMN prosthetic group of NADH-Q oxidoreductase (Complex I), the first of four complexes. This oxidoreductase also contains Fe-S centers. The electrons emerge in QH2, the reduced form of ubiquinone (Q). The citric acid cycle enzyme succinate dehydrogenase is a component of the succinate-Q reductase complex (Complex II), which donates electrons from FADH2 to Q to form QH2.This highly mobile hydrophobic carrier transfers its electrons to Q-cytochrome c oxidoreductase (Complex III), a complex that contains cytochromes h and c j and an Fe-S center. This complex reduces cytochrome c, a water-soluble peripheral membrane protein. Cytochrome c, like Q, is a mobile carrier of electrons, which it then transfers to cytochrome c oxidase (Complex IV). This complex contains cytochromes a and a 3 and three copper ions. A heme iron ion and a copper ion in this oxidase transfer electrons to O2, the ultimate acceptor, to form H2O. 

The enzyme, succinate dehydrogenase converts succinate to fumarate. For this reaction, malonic acid is a competitive inhibitor as it structurally resembles that of succinate. 

Stadie, W. C., and Haugaard, N., Oxygen poisoning. V. The effect of oxygen pressure upon enzymes succinic dehydrogenase and cytochrome oxidase. J. Biol. Chem. 161, 153-174 (1945). 

The existence of this enzyme, which means that hydrogen atoms from succinic acid can be passed directly on to flavin without travelling via NAD, represents the one major branch line so far found by which hydrogen atoms can be dispatched to oxygen but bypass NAD. It is not clear why the oxidation of succinic acid should proceed by a different pathway than that of most other substrates, but it is certain that the enzyme succinic dehydrogenase which catalyses the reaction is a fairly complex one. 

The succinate dehydrogenase complex (complex II) consists primarily of the citric acid cycle enzyme succinate dehydrogenase and two iron-sulfur proteins. Complex II mediates the transfer of electrons from succinate to UQ. The... 

In addition, feedback inhibition has two other characteristics that would be unlikely to arise haphazardly in longer pathways there is often very little structural resemblance between the end product that inhibits and the substrate of the inhibited enzyme and the inhibition is usually cooperative. Let us consider what these two properties mean. When inhibition arises for no obvious biological reason, it is usually for an obvious enough chemical reason the substrate and inhibitor are similar enough in terms of chemical structure that the inhibitor can bind to the same site on the enzyme as the one where the substrate binds however, as it lacks some feature necessary for the chemical reaction it does not react but does nothing. A classical example is provided by the enzyme succinate dehydrogenase, which uses succinate as its substrate but is inhibited by malonate (Figure 10.3). Succinate and malonate have almost the same chemical structures, so either is likely to bind to a site intended for... 

Fig. 10.3 Substrate and inhibitor. The reaction catalyzed by the enzyme succinate dehydrogenase alters the -CH2-CH2- gronping (shown with a gray background) in succinate. Malonate has a similar size and strnctnre, bnt does not have this grouping it interacts well with the gronps on the enzyme that allow snccinate to bind, and so it can be bound to the site of reaction bnt it caimot nndergo the reaction, so it is an inhibitor rather than a snbstrate...

Although enzymes catalyze only certain reactions or certain types of reaction, they are still subject to interference. When the activated complex is formed, the substrate is adsorbed at an active site on the enzyme. Other substances of similar size and shape may be adsorbed at the active site. Although adsorbed, they will not undergo any transformation. However, they do compete with the substrate for the active sites and slow down the rate of the catalyzed reaction. This is called competitive inhibition. For example, the enzyme succinic dehydrogenase will specifically catalyze the dehydrogenation of succinic acid to form fumaric acid. But other compounds similar to succinic acid will competitively inhibit the reaction. Examples are other diprotic acids such as malonic and oxalic acids. Competitive inhibition can be reduced by increasing the concentration of the substrate relative to that of the interferent so that the majority of enzyme molecules combine with the substrate. 

Llavin adenine dinucleotide (PAD) is a prosthetic group that participates in several intracellular oxidation-reduction reactions. During the catalytic cycle of the enzyme succinate dehydrogenase, PAD accepts two electrons from succinate, yielding fumarate as a prodnct. Becanse PAD is tightly bound to the enzyme, the reaction is sometimes shown this way... 

Succinate + FAD (enzyme bound) <=> Fumarate + FADH2 Enzyme Succinate Dehydrogenase... 

Complex II (succinate dehydrogenase) - Complex II is not in the path traveled by electrons from Complex I (Figure 15.3). Instead, it is a point of entry of electrons from FADH2 produced by the enzyme succinate dehydrogenase in the citric acid cycle. Both complexes I and II donate their electrons to the same acceptor, coenzyme Q. Complex II, like complex I, contains iron-sulfur proteins, which participate in electron transfer. It is also called succinate-coenzyme Q reductase because its electrons reduce coenzyme Q. 

Succinate is an intermediate of the citric acid cycle (and the glyoxylate cycle) produced by action of the enzyme succinyl-CoA synthetase on succinyl-CoA. Succinate is converted to fumarate by action of the enzyme succinate dehydrogenase (with formation of FADH2)... 

The enzyme is unable to bind both S and I at the same time and in competitive inhibition, the enzyme-inhibitor complex El does not react with substrate S. Competitive inhibitors often resemble substrate structurally. As an example we can mention malonate, which is an inhibitor for dehydrogenation of succinate of a enzyme succinic dehydrogenase and resembles the structure of succinate (Figure 6.35)... 

Step 6. Formation of Fumarate—FAD-Linked Oxidation Succinate is oxidized to fumarate, a reaction that is catalyzed by the enzyme succinate dehydrogenase. This enzyme is an integral protein of the inner mitochondrial membrane. We shall have much more to say about the enzymes bound to the inner mitochondrial membrane in Ghapter 20. The other individual enzymes of the citric acid cycle are in the mitochondrial matrix. The electron acceptor, which is FAD rather than NADA is covalently bonded to the enzyme succinate dehydrogenase is also called a flavoprotein because of the presence of FAD with its flavin moiety. In the succinate dehydrogenase reaction, FAD is reduced to FADHo and succinate is oxidized to fumarate. 

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