Succinic dehydrogenase, action

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. 

Enzymes are usually impressively specific in their action. The specificity toward substrate is sometimes almost absolute. For many years urea was believed to be the only substrate for the enzyme urease and succinate the only substrate for succinate dehydrogenase. Even after much searching for other substrates, only... 

Kato and coworkers have made an extensive study of the mechanism of action of cord factor (see p. 210) and have found a significant decrease of the activity of the succinic and malic dehydrogenase systems of the liver of mice, about twenty-four hours after intraperitoneal injection of 0.1 mg. This finding seems to be related to the work of Martin and coworkers, who reported a decrease of succinic dehydrogenase activity in the kidneys of tuberculous guinea-pigs. 

Many metabolic processes such as glycolysis, Krebs cycle reactions, photosynthesis, protein synthesis, and lipid metabolism are affected by exposure to F. Much of the action of F on these processes can be attributed to F-dependent inhibition of enzymes. Examples of enzymes shown to be inhibited by F include enolase, phosphoglucomutase, phosphatase, hexokinase, PEP carboxylase, pyruvate kinase, succinic dehydrogenase, malic dehydrogenase, pyrophosphatase, phytase, nitrate reductase, mitochondrial ATPase, urease (Miller et al. 1983), lipase (Yu et al. 1987), amylase (Yu et al. 1988), invertase (Yu 1996 Ouchi et al. 1999), and superoxide dismutase (SOD) (Wilde and Yu 1998). 

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)... 

Oxaloacetate is derived from succinate by the sequential action of succinate dehydrogenase, fumarase, and malate dehydrogenase. When levels of oxaloacetate are high, one would expect the activity of the enzyme to be reduced. Low levels of oxaloacetate would call for an increase in succinate production. 

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. 

A structurally very similar molecule, tiadinil (11, Fig. 13.3.2), has been shown to have another mode of action as it is an activator of systemic acquired resistance and induces defense gene expression [13]. This illustrates that succinate dehydrogenase inhibitors cannot be recognized based on their structure alone. 

Carboxin inhibits, to a different degree, succinate dehydrogenase of such diverse organisms as fungi, bacteria, plants and mammals, and the study of resistant mutants has contributed to understanding the mechanism of action [35]. Additional information stems from Saccharomyces and bacteria [36-38]. 

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). 

The literature confirms that attempts to clarify the mechanism of silver nanoparticle action against bacteria, viruses, and fungi have been taken. One of the most common mechanisms of nanosilver antibacterial activity is based on its natural affinity for bonding with a thiol group present in cysteine, which is a protein building material of bacterial cell walls. Consequently, the enzymatic function of the proteins is disturbed and the cellular respiration chain is interrupted. At the same time other enzymes such as NADH and succinate dehydrogenase are destroyed (Park et al., 2009). 

The clear detection of both reversible active-site and biocatalytic waves represents a completeness that establishes the feasibility of applying direct elec-tochemistry to probe the mechanism of action of complex redox enzymes. To take this further, I shall take up the author s prerogative for mentioning studies currently underway in the laboratory and mention, briefly, another membrane-bound enzyme, fumarate reductase (FR), isolated from Escherichia coll Structurally, this is closely related to the more familiar succinate dehydrogenase (SDH) which constitutes the major part of Complex II of the mitochondrial respiratory chain. Of the four subunits which make up the membrane-bound system, two may be freed to give a soluble enzyme that is active in fumarate reduction by artificial electron donors [230]. The larger of these, MW approx. 70000, contains, like SDH, a covalently bound FAD. The smaller, MW approx. 30000, appears to contain three Fe-S clusters. These are termed centre 1 ([2Fe-2S]), centre 2 ([4Fe-4S]) and centre 3 ([3Fe-4S]). Their respective reduction potentials as determined by potentiometry are — 20 mV, — 320 mV, and — 70 mV [231], (Although the potential of the FAD has not been determined for FR, the two-electron value for beef heart SDH is — 79 mV at pH 7.0. The radical form is unstable since the two one-electron reductions occur at potentials of — 127 and — 31 mV respectively [232].)... 

Iron is necessary for enzyme activity the activity decreases with the amount of iron lost in the preparation. Therefore, it is tempting to assume that iron acts as an electron carrier. The successive reduction and oxidation of the iron in the course of succinic oxidation have never been demonstrated, but the action of many inhibitors on the succinic dehydrogenase system can be explained by assuming the formation of metal complexes. 

In spite of the fact that succinic dehydrogenase has been known to exist for half a century and that many laboratories have attempted to study its mode of action, little is known of its mode of regulation. The 23 amino acids adjacent to the flavin have been sequenced. 

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