Succinic acid dehydrogenase inhibition

Wood and coworkers have demonstrated that pigeon liver mince poisoned with malonate is unable to convert C 02 into isotopic succinate but can direct the isotope into malate and fumarate as well as into the a-carboxyl of a-ketoglutarate (see Fig. 5). On the other hand, non-poisoned liver possesses the ability to anaerobically fix C 02 in succinic acid as well as fumaric and malic acids. The dicarboxylic acids invariably contain the isotopic carbon predominantly in their respective carboxyl groups. These important experiments provide conclusive proof for two main concepts. First, that malonate specifically inhibits succinic acid dehydrogenase and hence blocks completely the formation of succinic from fumaric acid. Secondly, there must be two routes by which succinate is formed. By the first pathway, pyruvate can condense with... 

The microbiostatic action of benzoic acid is based on different inhibition mechanisms, mainly many enzymes in the microbial cell are inhibited (Bosund, 1962 Menon et al., 1990). E.g. in yeast, enzymes that control the acetic acid metabolism and oxidative phosphorylation are inhibited. Benzoic acid appears to intervene at various points in the citric acid cycle, especially that of a-ketoglutaric acid and succinic acid dehydrogenase. Besides its enzyme-inactivating effects, benzoic acid also acts on the cell wall. The types of action of benzoic acid are sometimes very similar to those of sorbic acid, although many more data exist for the latter. 

Benzoic acid activity is directed both to cell walls and to inhibition of citrate cycle enzymes (a-ketoglutaric acid dehydrogenase, succinic acid dehydrogenase) and of enz)mies involved in oxidative phosphorylation. 

The addition of malonate, a specific inhibitor of the succinic dehydrogenase system, inhibits the regeneration of oxalacetic acid and results in the accumulation of citric, a-ketoglutaric and succinic acids. Upon exhaustion of the remaining stores of oxalacetic acid, pyruvate oxidation in muscle ceases and can only be resumed after further addition of oxalacetic acid or addition of any dicarboxylic acid capable of conversion to oxalacetic acid. Under these conditions, the amount of pyruvate oxidized is equivalent to the amount of oxalacetate supplied. 

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. 

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. 

Valproic Acid (Depakote) A fatty acid which inhibits GABA-transaminase and succinic semialdehyde dehydrogenase, the enzymes which degrade GABA. Preferred drug for seizure disorders which have components of more than one seizure type. Therapeutic serum levels are 50-100 jg/ml. Toxicity Tremor and sedation. Metab 90% protein bound. Metabolites inactive. 

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... 

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). 

GABA is metabolized by GABA-T to succinic semialdehyde, which IS further oxidized by succinic semialdehyde dehydrogenase to succinic acid. Inhibition of GABA-T is therefore accompanied by an increase m GABA and this increase should reflect GABA turnover. The inhibition of GABA-T can be... 

The Oxaloacetic System (Szent-Gyoi i, 1937).— The wide distribution of the three enzymes, succinic and malic dehydrogenase, and fumarase, si ests that they and their respective substrates participate in many tissue respirations. Addition of malonic acid, which inhibits succinic acid oxidation, leads to an almost complete... 

The action of some inhibitors can be prevented or reversed by addition of more substrate the extent of inhibition depends upon the ratio of inhibitor to substrate concentration. The classical example of such a relationship is the inhibition of the enz5rme succinate dehydrogenase (this enzyme oxidises succinic acid) by malonic acid. The chemical similarity between substrate and inhibitor is clear from the formula of succinic and malonic acids (see page 104). 

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. 

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. ... 

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. 

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. 

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. 

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