Acid Cycle

Our subject in this chapter is the total degradation of glucose to CO2 and H2 O and the production of ATP which this degradation allows. Up to this point degradation has led to a 2-C body, active acetate. These last two C atoms must now be eliminated in the form of CO2 and that takes place in the citric acid cycle (Fig. 58). 

Active acetate is linked to a 4-C body, oxalacetate, by the condensing enzyme in a kind of aldol condensation. The product is citrate, which exists in equilibrium with c/s-aconitate and isocitrate, the equilibrium being controlled by aconitase. 

Isocitrate dehydrogenases transfer hydrogen from the secondary hydroxyl group of isocitrate to either NAD+or NADP. NADH + H+then 

Succinyl CoA synthetase (at the mention of this name we must not forget that enzymes catalyze reactions in the forward and in the backward direction) breaks down succinyl CoA into succinate and HS-CoA. In so doing, the energy of the thiol ester bond is used for the formation of ATP. At least that is so with the succinyl CoA synthetase from spinach. In animals, GTP is formed at this point, which then transfers its terminal phosphate residue to ADP, thus leading indirectly to ATP. 

In the next step nature shows us a trick which is to be found time and again water is first added across a double bond and then hydrogen is abstracted from the addition product. In the present case fumarate hy-dratase catalyzes the addition of water to the double bond of fumarate to give malate which is then dehydrogenated to oxalacetate by malate dehydrogenase. NAD serves as the hydrogen acceptor. 

034054 Malate synthase [Malate condensing enzyme, Glyoxy- 

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Glutamic acid is formed m most organisms from ammonia and a ketoglutaric acid a Ketoglutaric acid is one of the intermediates m the tricarboxylic acid cycle (also called the Krebs cycle) and arises via metabolic breakdown of food sources carbohy drates fats and proteins... 

Fig. 3. Biosynthetic pathways for amino acids. HMP = hexose monophosphate pathway CAC = citric acid cycle P = phosphate PP = pyrophosphate ...

L-glutamate dehydrogenase L-glutamate test for citric acid cycle... 

Physiological Role of Citric Acid. Citric acid occurs ia the terminal oxidative metabolic system of virtually all organisms. This oxidative metabohc system (Fig. 2), variously called the Krebs cycle (for its discoverer, H. A. Krebs), the tricarboxyUc acid cycle, or the citric acid cycle, is a metaboHc cycle involving the conversion of carbohydrates, fats, or proteins to carbon dioxide and water. This cycle releases energy necessary for an organism s growth, movement, luminescence, chemosynthesis, and reproduction. The cycle also provides the carbon-containing materials from which cells synthesize amino acids and fats. Many yeasts, molds, and bacteria conduct the citric acid cycle, and can be selected for thek abiUty to maximize citric acid production in the process. This is the basis for the efficient commercial fermentation processes used today to produce citric acid. 

Fig. 2. Kiebs (citiic acid) cycle. Coenzyme A is lepiesented CoA—SH. The cycle begins with the combination of acetyl coenzyme A and oxaloacetic acid to...

Citric acid cycle components (from rat heart mitochondria). 

FIGURE 18.2 The metabolic map as a set of dots and lines. The heavy dots and lines trace the central energy-releasing pathways known as glycolysis and the citric acid cycle. 

The combustion of the acetyl groups of acetyl-CoA by the citric acid cycle and oxidative phosphorylation to produce COg and HgO represents stage 3 of catabolism. The end products of the citric acid cycle, COg and HgO, are the ultimate waste products of aerobic catabolism. As we shall see in Chapter 20, the oxidation of acetyl-CoA during stage 3 metabolism generates most of the energy produced by the cell. 

Certain of the central pathways of intermediary metabolism, such as the citric acid cycle, and many metabolites of other pathways have dual purposes—they serve in both catabolism and anabolism. This dual nature is reflected in the designation of such pathways as amphibolic rather than solely catabolic or anabolic. In any event, in contrast to catabolism—which converges to the common intermediate, acetyl-CoA—the pathways of anabolism diverge from a small group of simple metabolic intermediates to yield a spectacular variety of cellular constituents. 

Catabolism converges via the citric acid cycle to three principal end products water, carbon dioxide, and ammonia. 

FIGURE 18.16 Compartmentalization of glycolysis, the citric acid cycle, and oxidative phosphorylation. 

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed. 

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. 

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