Oxidation citric acid cycle intermediates

This enzyme is found in many tissues, where it catalyzes the reversible oxidative deamination of the amino acid glutamate. It produces the citric acid cycle intermediate a-ketoglutarate, which serves as an entry point to the cycle for a group of glucogenic amino adds. Its role in urea synthesis and nitrogen removal is stiU controversial, but has heen induded in Figure 1-17-1 and Table 1-17-1. 

Zhao et al. (36) found that some citric acid metabolites are decreased in acute ischemia and acute myocardial disease. The citric acid plays an important role in oxidative phosphorylation and ATP production in the cardiomyo-cytes in which levels of citric acid cycle intermediates are supplied by glycolysis and (1-oxidation of fatty acids. 

Oxaloacetate, the product of the pyruvate carboxylase reaction, functions both as an important citric acid cycle intermediate in the oxidation of acetyl CoA and as a precursor for gluconeogenesis. The activity of pyruvate carboxylase depends on the presence of acetyl CoA so that more oxaloacetate is made when acetyl CoA levels rise. 

Glutamate is synthesized from NH4 + and a-ketoglutarate, a citric acid cycle intermediate, by the action of glutamate dehydrogenase. We have already encountered this enzyme in the degradation of amino acids (Section 23.3.1). Recall that NAD+ is the oxidant in catabolism, whereas NADPH is the reductant in biosyntheses. Glutamate dehydrogenase is unusual in that it does not discriminate between NADH and NADPH, at least in some species. 

Amphibolic pathways can function in both anabolic and catabolic processes. The citric acid cycle is obviously catabolic, because acetyl groups are oxidized to form C02 and energy is conserved in reduced coenzyme molecules. The citric acid cycle is also anabolic, because several citric acid cycle intermediates are precursors in biosynthetic pathways (Figure 9.10). For example,... 

When citrate, a citric acid cycle intermediate, moves from the mitochondrial matrix into the cytoplasm, it is cleaved to form acetyl-CoA and oxaloacetate by citrate lyase. The citrate lyase reaction is driven by ATP hydrolysis. Most of the oxaloacetate is reduced to malate by malate dehydrogenase. Malate may then be oxidized to pyruvate and CO, by malic enzyme. The NADPH produced in this reaction is used in cytoplasmic biosynthetic processes, such as fatty acid synthesis. Pyruvate enters the mitochondria, where it may be converted to oxaloacetate or acetyl-CoA. Malate may also reenter the mitochondria, where it is reoxidized to form oxaloacetate. 

Although most fatty acids contain an even number of carbon atoms, some organisms (e.g., some plants and microorganisms) produce odd-chain fatty acid molecules. /3-Oxidation of such fatty acids proceeds normally until the last /3-oxidation cycle, which yields one acetyl-CoA molecule and one propionyl-CoA molecule. Propionyl-CoA is then converted to succinyl-CoA, a citric acid cycle intermediate (Figure 12B). Ruminant animals such as cattle and sheep... 

The citric acid cycle is an important component of aerobic respiration. The NADH and FADH, produced during oxidation-reduction reactions of the cycle donate electrons to the mitochondrial ETC. Citric acid cycle intermediates are also used as biosynthetic precursors. 

The carbon skeletons of amino acids can be converted to citric acid cycle intermediates and completely oxidized to produce ATP energy. 

Citrate is also an allosteric inhibitor of phosphofmctokinase. A high concentration of citrate (a citric acid cycle intermediate) in a cell signals that the cell is currently meeting its energy needs by the oxidation of fats and proteins, so the oxidation of carbohydrates can be stopped temporarily. 

Glycolysis and the citric acid cycle (to be discussed in Chapter 20) are coupled via phosphofructokinase, because citrate, an intermediate in the citric acid cycle, is an allosteric inhibitor of phosphofructokinase. When the citric acid cycle reaches saturation, glycolysis (which feeds the citric acid cycle under aerobic conditions) slows down. The citric acid cycle directs electrons into the electron transport chain (for the purpose of ATP synthesis in oxidative phosphorylation) and also provides precursor molecules for biosynthetic pathways. Inhibition of glycolysis by citrate ensures that glucose will not be committed to these activities if the citric acid cycle is already saturated. 

As its name implies, the citric acid cycle is a closed loop of reactions in which the product of the hnal step (oxaloacetate) is a reactant in the first step. The intermediates are constantly regenerated and flow continuously through the cycle, which operates as long as the oxidizing coenzymes NAD+ and FAD are available. To meet this condition, the reduced coenzymes NADH and FADH2 must be reoxidized via the electron-transport chain, which in turn relies on oxygen as the ultimate electron acceptor. Thus, the cycle is dependent on the availability of oxygen and on the operation of the electron-transport chain. 

Steps 7-8 of Figure 29.12 Hydration and Oxidation The final two steps in the citric acid cycle are the conjugate nucleophilic addition of water to fumarate to yield (S)-malate (L-malate) and the oxidation of (S)-malate by NAD+ to give oxaloacetate. The addition is cataiyzed by fumarase and is mechanistically similar to the addition of water to ris-aconitate in step 2. The reaction occurs through an enolate-ion intermediate, which is protonated on the side opposite the OH, leading to a net anti addition. 

The amino acids are required for protein synthesis. Some must be supplied in the diet (the essential amino acids) since they cannot be synthesized in the body. The remainder are nonessential amino acids that are supplied in the diet but can be formed from metabolic intermediates by transamination, using the amino nitrogen from other amino acids. After deamination, amino nitrogen is excreted as urea, and the carbon skeletons that remain after transamination (1) are oxidized to CO2 via the citric acid cycle, (2) form glucose (gluconeogenesis), or (3) form ketone bodies. 

The citric acid cycle is the final common pathway for the aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but the hver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported such ab-normahties would be incompatible with life or normal development. 

These include the mitochondrial respiratory chain, key enzymes in fatty acid and amino acid oxidation, and the citric acid cycle. Reoxidation of the reduced flavin in oxygenases and mixed-function oxidases proceeds by way of formation of the flavin radical and flavin hydroperoxide, with the intermediate generation of superoxide and perhydroxyl radicals and hydrogen peroxide. Because of this, flavin oxidases make a significant contribution to the total oxidant stress of the body. 

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