Citric acid cycle, reactions succinate oxidation

FIGURE 16-22 Relationship between the glyoxylate and citric acid cycles. The reactions of the glyoxylate cycle (in glyoxysomes) proceed simultaneously with, and mesh with, those of the citric acid cycle (in mitochondria), as intermediates pass between these compartments. The conversion of succinate to oxaloacetate is catalyzed by citric acid cycle enzymes. The oxidation of fatty acids to acetyl-CoA is described in Chapter 17 the synthesis of hexoses from oxaloacetate is described in Chapter 20. 

Synthesis of succinyl-CoA in mammalian cells such as the red cell and liver cell can be accomplished either from a-KG or from succinate. The formation of succinyl-CoA occurs in the mitochondria as part of the citric acid cycle reactions. The requirement for a citric acid cycle to form ALA or protoporphyrin or heme has been shown by tracer studies with acetate and succinate [39], and by inhibition studies with malonate, Ira j -aconitate, fluoracetate, and arsenite [49]. The requirement for an electron transfer system from the citric acid cycle to O2 has been shown by inhibition studies with anaerobiosis and CO. The requirement for oxidative phosphorylation has been shown by dinitrophenol inhibition of ALA synthesis dinitrophenol may also inhibit ALA-synthetase [3,49]. 

One of the first persons to study the oxidation of organic compounds by animal tissues was T. Thunberg, who between 1911 and 1920 discovered about 40 organic compounds that could be oxidized by animal tissues. Salts of succinate, fumarate, malate, and citrate were oxidized the fastest. Well aware of Knoop s (3 oxidation theory, Thunberg proposed a cyclic mechanism for oxidation of acetate. Two molecules of this two-carbon compound were supposed to condense (with reduction) to succinate, which was then oxidized as in the citric acid cycle to oxaloacetate. The latter was decarboxylated to pyruvate, which was oxidatively decarboxylated to acetate to complete the cycle. One of the reactions essential for this cycle could not be verified experimentally. It is left to the reader to recognize which one. 

Three modifications of the conventional oxidative citric acid cycle are needed, which substitute irreversible enzyme steps. Succinate dehydrogenase is replaced by fumarate reductase, 2-oxoglutarate dehydrogenase by ferredoxin-dependent 2-oxoglutarate oxidoreductase (2-oxoglutarate synthase), and citrate synthase by ATP-citrate lyase [3, 16] it should be noted that the carboxylases of the cycle catalyze the reductive carboxylation reactions. There are variants of the ATP-driven cleavage of citrate as well as of isocitrate formation [7]. The reductive citric acid... 

Acetyl-CoA is oxidized to C02 by the Krebs cycle, also called the tricarboxylic acid cycle or citric acid cycle. The origin of the acetyl-CoA may be pyruvate, fatty acids, amino acids, or the ketone bodies. The Krebs cycle may be considered the terminal oxidative pathway for all foodstuffs. It operates in the mitochondria, its enzymes being located in their matrices. Succinate dehydrogenase is located on the inner mitochondrial membrane and is part of the oxidative phosphorylation enzyme system as well (Chapter 17). The chemical reactions involved are summarized in Figure 18.7. The overall reaction from pyruvate can be represented by Equation (18.5) ... 

These reactions produce two important intermediate compounds, succinate and malate (which is converted into oxaloacetate). The two decarboxylation steps of the citric acid cycle are bypassed, and so there is no oxidation of acetyl-CoA to C02. Two molecules of acetyl-CoA are used, but all the carbon atoms are retained. 

We can now estimate how many molecules of ATP are formed when glucose is completely oxidized to GO2. The number of ATP (or GTP) molecules formed in glycolysis and the citric acid cycle is unequivocally known because it is determined by the stoichiometries of chemical reactions. In contrast, the AT P yield of oxidative phosphorylation is less certain because the stoi chiometries of proton pumping, ATP synthesis, and metabolite-transport processes need not be integer numbers or even have fixed values. As stated earlier, the best current estimates for the number of protons pumped out of the matrix by NADH-Q oxidoreductase, Q-cytochrome c oxidoreductase, and cytochrome c oxidase per electron pair are four, two, and four, respectively. The synthesis of a molecule of ATP is driven by the flow of about three protons through ATP synthase. An additional proton is consumed in transporting ATP from the matrix to the cytoplasm. Hence, about 2.5 molecules of cytoplasmic ATP are generated as a result of the flow of a pair of electrons from NADH to O2. For electrons that enter at the level of Q-cytochrome c oxidoreductase, such as those from the oxidation of succinate or cytoplasmic NADH, the yield is about 1.5 molecules of ATP per electron pair, Hence, as tallied in Table 18.4, about 30 molecules of ATP are formed... 

A FIGURE 2-25 Conversion of succinate to fumarate. In this oxidation reaction, which occurs in mitochondria as part of the citric acid cycle, succinate loses two electrons and two protons. These are transferred to FAD, reducing it to FADH2. 

Succinate-CoQ Reductase (Complex II) Succinate dehydrogenase, the enzyme that oxidizes a molecule of succinate to fumarate in the citric acid cycle, is an integral component of the succinate-CoQ reductase complex. The two electrons released in conversion of succinate to fumarate are transferred first to FAD, then to an iron-sulfur cluster, and finally to CoQ (see Figure 8-17). The overall reaction catalyzed by this complex is... 

Oxidation/reduction reactions involve the transfer of electrons from a molecule being oxidized (the electron donor) to a molecule being reduced (the electron acceptor). Because one or more electrons are transferred, neither oxidation nor reduction can occur without the other occurring simultaneously. An example of an oxidation/reduction reaction is the following reaction, catalyzed by succinate dehydrogenase, from the citric acid cycle ... 

---