Succinate dehydrogenase mechanism

Covalently Bound Flavins. The FAD prosthetic group in mammalian succinate dehydrogenase was found to be covalently affixed to protein at the 8 a-position through the linkage of 3-position of histidine (102,103). Since then, several covalently bound riboflavins (104,105) have been found successively from the en2ymes Hsted in Table 3. The biosynthetic mechanism, however, has not been clarified. 

Such a process is supposed to occur within the limits of Q-cycle mechanism (Figure 23.2). In accord with this scheme ubihydroquinone reduced dioxygen in Complex III, while superoxide producers in Complex I could be FMN or the FeS center [12]. Zhang et al. [24] also suggested that the Q-cycle mechanism is responsible for the superoxide production by the succinate-cytochrome c reductase in bovine heart mitochondria and that FAD of succinate dehydrogenase is another producer of superoxide. Young et al. [25] concluded that, in addition to Complex III, flavin-containing enzymes and FeS centers are also the sites of superoxide production in liver mitochondria. 

Ramaswama, R. and Sushella, L. (1974). A mechanism of thermogenesis by modification of succinate dehydrogenase. In Biomembranes. Architecture, Biogenesis, Bioenergetics and Differentiation , pp.261-277. New York. 

R. Kevin et al., Mechanism of superoxide and hydrogen peroxide formation by fumarate reductases, succinate dehydrogenase, aspartate oxidase. J. Biol. Chem. 277, 42563 12571 (2002)... 

Effects of Mutations in Mitochondrial Complex II Single nucleotide changes in the gene for succinate dehydrogenase (Complex II) are associated with midgut carcinoid tumors. Suggest a mechanism to explain this observation. 

At the active site of beef heart mitochondrial succinate dehydrogenase (EC 1.3.99.1), the FAD is covalently linked by C-8a to nitrogen of a histidine residue (Fig. 2b) [20]. In the catalytic reaction, removal of a proton from C-3 of the succinate may be followed by attack of the 3-carbanion on N-5 of the FAD to form an intermediate adduct, which breaks down with loss of a proton from C-2 of the succinate, giving fumarate and a reduced FAD moiety [21]. This mechanism is not certain, but it is established that the succinate loses two non-equivalent hydrogen atoms by a trans elimination (Fig. 4) [22], In other enzymes, different types of covalent attachment of the FAD are known [23]. 

It has been known since the early studies of Kearney (192) that succinate dehydrogenase undergoes reversible activation by substrates, competitive inhibitors, and phosphate. The activation of succinate dehydrogenase was shown to be a characteristic of both the soluble and particle-bound enzyme and a slow process requiring many minutes of incubation with the activator at ambient or higher temperatures (activation energy = 31-33 kcal/mole). It has been suggested that the enzyme exists in a free equilibrium between the unactivated and the activated forms, and that the activator interacts with the latter and establishes a new equilibrium in favor of the activated state of the enzyme (23, 25, 193 see also 194 for an expanded mechanism). 

Study of the reaction mechanism of succinate dehydrogenase has. been complicated, partly because of the activation-deactivation properties of the enzyme, and partly because most of the early preparations studied had low iron content and low activities. Kinetic studies with activated, soluble preparations have led Zeylemaker et al. [215) to propose the fol-... 

The intermediate EiP, which is the major species of reduced enzyme with which O2 reacts in the amino acid oxidase reaction, is more reactive with O2 than Er in one case (49) (D-amino acid oxidase) but less reactive in the other (18) (n-amino acid oxidase). The reasons for such seemingly inconsistent behavior, as well as the virtual lack of reactivity of reduced flavins with O2 in systems such as succinic dehydrogenase, will only become clear when the molecular details of the oxidation mechanism of reduced flavin are elucidated. 

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. 

The exact mechanism of toxicity is not clear. In vitro studies suggested that incubation of dichlone with normal human erythrocytes induced rapid loss of intracellular potassium, increased the osmotic fragility, and inhibited the Na, K + -ATPase. Dietary dichlone exposure caused inhibition of glycolysis in rat liver. Dichlone can inhibit pyruvate and succinate dehydrogenases. Dichlone was also reported to cause oxidative stress and swelling of mitochondria. 

Lewisite shares many biochemical mechanisms of injury with the other arsenical compounds. It inhibits many enzymes in particular, those with thiol groups, such as pyruvic oxidase, alcohol dehydrogenase, succinic oxidase, hexokinase, and succinic dehydrogenase. As is tme with mustard, the exact mechanism by which Lewisite damages cells has not been completely defined. Inactivation of carbohydrate metabolism, primarily because of inhibition of the pymvate dehydrogenase complex, is thought to be a key factor (Trammel, 1992). 

Fig. 21.5. Components of the electron transfer chain. NADH dehydrogenase (complex 1) spans the membrane and has a proton pumping mechanism involving CoQ. The electrons go from CoQ to c5riochrome b-cl complex (complex El), and electron transfer does NOT involve complex II. Succinate dehydrogenase (complex II), glycerol 3-phosphate dehydrogenase, and ETF Q oxidoreductase (shown in blue) all transfer electrons to CoQ, but do not span the membrane and do not have a proton pumping mechanism. As CoQ accepts protons from the matrix side, it is converted to QH2. Electrons are transferred from complex III to complex IV (cytochrome c oxidase) by cytochrome c, a small cytochrome in the intermembrane space that has reversible binding sites on the b-c, complex and cytochrome c oxidase.

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