Succinic acid dehydrogenase, competitive

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. 

Malonic acid is a classical example of a true competitive inhibitor. Malonic acid inhibits succinic dehydrogenase, which catalyzes the oxidation of succinic acid to fumaric acid, as shown below. 

The next relevant discovery was made in 1910, when it was noted that some enzymes are blocked by substances whose molecular structure resembles that of the normal substrates. Thus amylase, which normally hydrolyses starch, is inhibited by glucose (see Section 9.1). Again, malonic acid 9.3) competitively inactivates the enzyme succinic dehydrogenase by displacing the normal substrate, succinic acid 9.4), from the enzyme (Quastel and Wooldridge, 1927). A similar phenomenon in physiology is the toxic action of carbon monoxide... 

Valproic acid and its salts are a new group of antiepileptic drugs that differs from the known drugs both structurally and in terms of its mechanism of action. It is believed that it acts on the metabolism of the GABA system. Valproic acid has been shown to elevate the level of GABA in the brain by means of competitive inhibition of GABA transaminase and the dehydrogenase of succinic semialdehyde. 

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. 

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

Compound (LVII) is very rapidly excreted into the kidney. It is metabolised to 5-(3 -hydroxy-4 -aminophenyl)cytosine and its O-glucuronide, as well as derivatives acetylated on both amino groups [343]. It is a competitive inhibitor of succinate dehydrogenase (K = 9-2 x 10 m K,- = 5 0 X IO m), and it has been considered that this is its mode of action [343]. One role of this enzyme involves aspartate synthesis, via fumarate. This pyrimidine enhances the incorporation of orotic acid into nucleic acid but is not itself incorporated. 

Malonic add HOOC-CH2-COOH, a dicarboxyl-ic acid, m.p. 135.6 °C, which has been found in the free form in plants, but is of only sporadic occurrence. At the pH of the cell M.a. is present as its anion (mal-onate), which is a known competitive inhibitor of succinate dehydrogenase in the tricarboxylic acid cycle. A metabolically important derivative of M.a. is malo-nyl-CoA, an intermediate of Fatty acid biosynthesis (see). 

The efficiency of an enzyme can be reduced or can even become negligible in the presence of certain substances, known as inhibitors. Many inhibitors have structural resemblances with the substrates and compete with them for the formation of complexes with the enzyme. This is the case of the inactivation of cytochrome c oxidase by the cyanide ion, which blocks the mitochondrial electron-transport chain to oxygen. Similarly, the inactivation of the succinate dehydrogenase by malonate involves its inhibition of the conversion of succinate to fumarate in the citric acid cycle. In the latter case, the mechanism for competitive inhibition is... 

When an inhibitor acts to reduce the concentration of the available fee enzyme for the substrate binding, it is said that competitive inhibition takes place. An eminent example is that of succinate dehydrogenase, which is competitively inhibited by malonate to convert succinate to fiimarate within the citric acid cycle (Walsh, 1979 Voet Voet, 1995). 

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