Succinate dehydrogenase, inhibition

Iron is also an essential constituent of several non-porphyrin enzymes, e.g. aconitase, aldolase, and succinic dehydrogenase. Inhibition of the synthesis of glucose by tryptophan in animal cells depends on chelation. The tryptophan is metabolized to pyridine-2,3-dicarboxylic acid, which complexes the divalent iron necessary for the action of phosphoenolpyruvate carboxykinase (a key enzyme in the neogenesis of glucose) (Veneziale et al., 1967). 

Succinate Dehydrogenase—A Classic Example of Competitive Inhibition... 

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. 

Barbiturates such as amobarbital inhibit NAD-hnked dehydrogenases by blocking the transfer from FeS to Q. At sufficient dosage, they are fatal in vivo. Antin cin A and dimercaprol inhibit the respiratory chain between cytochrome b and cytochrome c. The classic poisons H2S, carbon monoxide, and cyanide inhibit cytochrome oxidase and can therefore totally arrest respiration. Malonate is a competitive inhibitor of succinate dehydrogenase. 

Abe K, Saito H. Amyloid beta protein inhibits cellular MTT reduction not by suppression of mitochondrial succinate dehydrogenase but by acceleration of MTT formazan exocytosis in cultured rat cortical astrocytes. Neurosci Res 1998 31 295-305. 

In addition to binding to cytochrome c oxidase, cyanide inhibits catalase, peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, and succinic dehydrogenase activities. These reactions may make contributions to the signs of cyanide toxicity (Ardelt et al. 1989 Rieders 1971). Signs of cyanide intoxication include an initial hyperpnea followed by dyspnea and then convulsions (Rieders 1971 Way 1984). These effects are due to initial stimulation of carotid and aortic bodies and effects on the central nervous system. Death is caused by respiratory collapse resulting from central nervous system toxicity. 

Gasper GM and Kawatski JA. 1972. Inhibition by heptachlor epoxide of succinic dehydrogenase activity in mouse liver homogenates. Comp Biochem Physiol 41 655-660. 

Administration of 1 and 3 mg Sn/kg body weight to rats resulted in inhibition of various enzymes, including hepatic succinate dehydrogenase and the acid phosphatase of the femoral epiphysis. Tin also appears to interact with the absorption and metabolism of biological essential metals such as copper, zinc, and iron and to influence heme metabolism. ... 

Krebs cycle Inhibition of aconitase by superoxide and fluoroacetate, of succinate dehydrogenase by methamphetamine and mal-onate, of alpha-ketoglutarate dehydrogenase by salicylic add... 

The activity of complex II (succinate dehydrogenase) is measured as the succinate-dependent reduction of decylubiquinone, which is in turn recorded spectro-photometrically through the reduction of dichlorophenol indophenol at 600 nm (e 19,100-M -cm Fig. 3.8.5). In order to ensure a linear rate for the activity, the medium is added with rotenone, ATP, and a high concentration of succinate. As noticed previously for complex I, decylubiquinone is not a perfect acceptor for electrons from the membrane-inserted complex II [70]. Malonate, a competitive inhibitor of the enzyme, is used to inhibit it. Rather than decylubiquinone, phenazine methosulfate can be utilized, which diverts the electrons from the complex before they are conveyed through subunits C and D, therefore allowing measurement of the activity of subunits A and B. 

Krebs cycle is inhibited at the points where a-ketoglutarate dehydrogenase and succinate dehydrogenase operate. This causes an increase in organic acids and an accumulation of glutamate. 

Correct answer = D. Thirteen of the approximately 100 polypeptides required for oxidative phosphorylation are coded for by mitochondrial DNA, including the electron transport components cytochrome c and coenzyme Q. Oxygen directly oxidizes cytochrome oxidase. Succinate dehydrogenase directly reduces FAD. Cyanide inhibits electron flow, proton pumping, and ATP synthesis. 

Succinate is oxidized to fumarate by succinate dehydrogenase, pro ducing the reduced coenzyme FADH2 (see Figure 9.6). [Note FAD, rather than NAD, is the electron acceptor because the reducing power of succinate is not sufficient to reduce NAD. ] Succinate dehydrogenase is inhibited by oxaloacetate. 

Succinyl CoA is cleaved by succinate thiokinase (also called succinyl CoA synthetase), producing succinate and ATP (or GTP). This is an example of substrate-level phosphory lation. Succinate is oxidized to fumarate by succinate dehydrogenase, producing FADH2. The enzyme is inhibited by oxaloacetate. Fumarate is hydrated to malate by fumarase (fumarate hydratase), and malate is oxidized to oxaloacetate by malate dehy drogenase, producing NADH. 

At very high substrate concentrations deviations from the classical Michaelis-Menten rate law are observed. In this situation, the initial rate of a reaction increases with increasing substrate concentration until a limit is reached, after which the rate declines with increasing concentration. Substrate inhibition can cause such deviations when two molecules of substrate bind immediately, giving a catalytically inactive form. For example, with succinate dehydrogenase at very high concentrations of the succinate substrate, it is possible for two molecules of substrate to bind to the active site and this results in non-functional complexes. Equation S.19 gives one form of modification of the Michaelis-Menten equation. 

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. 

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. 

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. 

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