Succinate dehydrogenase structure

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. 

FIGURE 14.14 Structures of succinate, the substrate of succinate dehydrogenase (SDH), and malouate, the competitive inhibitor. Fumarate (the product of SDH action on succinate) is also shown. 

In addition to these more-or-less well characterized proteins, iron is known to be bound to certain flavoproteins such as succinic dehydrogenase (20), aldehyde oxidase (27), xanthine oxidase (22) and dihydrooro-tate dehydrogenase (23). Iron is present and functional in non-heme segments of the electron transport chain but again no real structural information is at hand (24). 

Aspartate can be deaminated to fumarate by bacterial L-aspartate oxidase.2593 This flavoprotein is structurally and mechanistically related to succinate dehydrogenase and can function as a soluble fumarate reductase (p. 1027). However, its main function appears to be to permit the intermediate iminoaspartate to react with dihydroxyacetone-P to form quinolinate, which can be converted to NAD (see Fig. 25-ll).259b... 

Competitive inhibitors often closely resemble in some respect the substrate whose reactions they inhibit and, because of this structural similarity, compete for the same binding site on the enzyme. The enzyme-inhibitor complex either lacks the appropriate reactive groups or is held in an unsuitable position with respect to the catalytic site of the enzyme which results in a complex which does not react (i.e. gives a dead-end complex). The inhibitor must first dissociate before the true substrate may enter the enzyme and the reaction can take place. An example is malonate, which is a competitive inhibitor of the reaction catalysed by succinate dehydrogenase. Malonate has two carboxyl groups, like the substrate, and can fill the substrate binding site on the enzyme. The subsequent reaction, however, requires that the molecule be reduced with the formation of a double bond. If malonate is the substrate, this cannot be achieved without the loss of one of the carboxy-groups and therefore no reaction occurs. 

NADH dehydrogenase and succinate dehydrogenase also contain Fe atoms that are bound by the S atoms of cysteine residues of the protein, in association with additional, inorganic sulfide atoms. Structures of these complexes are shown in figure 10.19. Succinate dehydrogenase has three iron-sulfur centers, one with a [2Fe-2S] cluster, one with [4Fe-4S], and one with a cluster containing 3 Fe atoms and 3 (or possibly 4) sulfides. Iron-sulfur centers undergo one-electron oxidation-reduction reactions. 

Table 29 Subunit Structures and Other Properties of Fumarate Reductase and Succinate Dehydrogenase from...

Fumarate is able to serve as an electron acceptor in anaerobic respiration, as it may be reduced reversibly to succinate in a two-electron process. The succinate-fumarate couple may therefore be utilized as an oxidant or reductant in the respiratory chain, and so differs from the other examples given in this section. These two reactions are catalyzed by succinate dehydrogenase and fumarate reductase, which have many similarities in subunit structure. These are shown in Table 29. Although they are different enzymes, the fumarate reductase can substitute for succinate dehydrogenase under certain conditions. The synthesis of succinate dehydrogenase is induced... 

Figure 7.3 The similarity of the structures of malonate and succinate explains why malonate inhibits succinate dehydrogenase...

The classic example of competitive inhibition is inhibition of succinate dehydrogenase, an enzyme, by the compound malonate. Hans Krebs first elucidated the details of the citric acid cycle by adding malonate to minced pigeon muscle tissue and observing which intermediates accumulated after incubation of the mixture with various substrates. The structure of malonate is very similar to that of succinate (see Figure 1). The enzyme will bind malonate but cannot act further on it. That is, the enzyme and inhibitor form a nonproductive complex. We call this competitive inhibition, as succinate and malonate appear to compete for the same site on the enzyme. With competitive inhibition, the percent of inhibition is a function of the ratio between inhibitor and substrate, not the absolute concentration of inhibitor. 

Ackrell BAC, Johnson MK, Gunsalus RP, Cecchini G (1992) Structure and function of succinate dehydrogenase and fumarate reductase. In Muller F (ed) Chemistry and biochemistry of flavoenzymes, vol III. CRC, Boca Raton, pp 229-297 Allen PC (1973) Helminths comparison of their rhodoquinone. Exp Parasitol 34 211-219... 

A classic example of competitive inhibition is the inhibition of succinate dehydrogenase by malonate, a structural analogue of succinate. Competitive inhibitors are usually structural analogues of the substrate, the molecule with which they are competing. They bind to the active site but either do not have a structure that is conducive to enzymatic modification or do not induce the proper orientation of catalytic amino acyl residues required to affect catalysis. Consequently, they displace the substrate from the active site and thereby depress the velocity of the reaction. Increasing [S] will displace the inhibitor. 

There are two Krebs cycle inhibitors that are worth mentioning. Malonate inhibits succinate dehydrogenase because of its very similar structure. Fluoro-acetate inhibits cis-aconitase, which is an Fe-S enzyme. The fluoroacetate replaces acetate as a substrate in the citrate synthase reaction when this combines with cis-aconitase, however, no further reaction becomes possible. 

A competitive inhibitor of an enzyme will typically structurally resemble a substrate of the enzyme. Thus malonate (methanedicarboxylate OOC-CH2-COO ) is structurally similar to succinate (ethanedicarboxylate OOC CH2 CH2 COO ) and is a competitive inhibitor of the oxidoreductase succinate dehydrogenase that catalyses the reaction ... 

Fia. 28. Structure of histidyl-8-o-FAD (left) and the sequence of the flavin penta-peptide (right) of succinate dehydrogenase. From Singer et al. (SB). 

Ackrell, B. A. C., Johnson, M. K., Gunsalus, R. P., and Cecchini, G., 1992, Structure and function of succinate dehydrogenase and fumarate reductase, in Chemistry and Biochemistry of Flavoenzymes, Volume 3 (E. Muller, ed.) CRC Press, Boca Raton, FL, pp. 229n297. 

X-ray crystal structures are available for cubane-type [3Fe-4S] centers in 3Fe and 7Fe Fds, aconitase, NiFe-hydrogenases, succinate dehydrogenase, fumarate... 

Examples of Rapid Reversible Inhibitors. Competitive inhibitors are often similar in structure to one of the substrates of the reaction they are inhibiting. Inhibitors of this type are sometimes called substrate analogs and their binding affinity (K ) usually approximates that of the substrate. One of the first reactions inhibited by a substrate analog was that catalyzed by succinate dehydrogenase (Equation 17.24). 

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

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