Oxidative citric acid cycle

This cyclic pathway was first proposed for Chlorobium sp. that use an anoxygenic photosynthesis for energy supply [3]. It reverses the reactions of the oxidative citric acid cycle (Krebs cycle) and forms acetyl-CoA from two C02 (Figure 3.2). 

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... 

This complete oxidative cycle is found in a number of archaebacteria. Halophiles can fulfil their energy requirements by metabolism of amino acids and other nitrogenous compounds, and therefore it is probable that they possess an oxidative citric acid cycle. Aitken and Brown [45] have reported the presence of the cycle s enzymes in Halobacterium halobium and we have found the key enzymes, citrate synthase and succinate thiokinase, in a range of classical and alkaliphilic halophiles [46], Thus, it is probable that the cycle is generally present in this group of archaebacteria, but exhaustive studies have not been carried out. 

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. 

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. 

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

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. 

Oxidation of 2 molecules of glyceraldehyde-3-phosphate yields 2 NADH Pyruvate conversion to acetyl-CoA (mitochondria) 2 NADH Citric acid cycle (mitochondria) 2 molecules of GTP from 2 molecules of succinyl-CoA + 2 + 2... 

The citric acid cycle, a nine-step process, also diverts chemical energy to the production of ATP and the reduction of NAD and FAD. In each step of the citric acid cycle (also known as the Krebs cycle) a glucose metabolite is oxidized while one of the carrier molecules, NAD or FAD, is reduced. Enzymes, nature s chemical catalysts, do a remarkable job of coupling the oxidation and reduction reactions so that energy is transferred with great efficiency. 

Stage 3 Acetyl CoA is oxidized in the citric acid cycle to give CO2-... 

Most fatty acids have an even number of carbon atoms, so none are left over after /3-oxidation. Those fatty acids with an odd number of carbon atoms yield the three-carbon propionyl CoA in the final j3-oxidation. Propionyl CoA is then converted to succinate by a multistep radical pathway, and succinate enters the citric acid cycle (Section 29.7). Note that the three-carbon propionyl group should properly be called propnnoyl, but biochemists generally use the non-systematic name. 

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 final step is the oxidation of (S)-malate by NAD+ to give oxaloacetate, a reaction catalyzed by malate dehydrogenase. The citric acid cycle has now returned to its starting point, ready to revolve again. The overall result of the cycle is... 

Ethanol is oxidized by alcohol dehydrogenase (in the presence of nicotinamide adenine dinucleotide [NAD]) or the microsomal ethanol oxidizing system (MEOS) (in the presence of reduced nicotinamide adenine dinucleotide phosphate [NADPH]). Acetaldehyde, the first product in ethanol oxidation, is metabolized to acetic acid by aldehyde dehydrogenase in the presence of NAD. Acetic acid is broken down through the citric acid cycle to carbon dioxide (CO2) and water (H2O). Impairment of the metabolism of acetaldehyde to acetic acid is the major mechanism of action of disulfiram for the treatment of alcoholism. 

Generally, NAD-linked dehydrogenases catalyze ox-idoreduction reactions in the oxidative pathways of metabolism, particularly in glycolysis, in the citric acid cycle, and in the respiratory chain of mitochondria. NADP-linked dehydrogenases are found characteristically in reductive syntheses, as in the extramitochon-drial pathway of fatty acid synthesis and steroid synthesis—and also in the pentose phosphate pathway. 

The nature of the diet sets the basic pattern of metabohsm. There is a need to process the products of digestion of dietary carbohydrate, lipid, and protein. These are mainly glucose, fatty acids and glycerol, and amino acids, respectively. In ruminants (and to a lesser extent in other herbivores), dietary cellulose is fermented by symbiotic microorganisms to short-chain fatty acids (acetic, propionic, butyric), and metabohsm in these animals is adapted to use these fatty acids as major substrates. All the products of digestion are metabohzed to a common product, acetyl-CoA, which is then oxidized by the citric acid cycle (Figure 15-1). 

Glucose is metabolized to pyruvate by the pathway of glycolysis, which can occur anaerobically (in the absence of oxygen), when the end product is lactate. Aerobic tissues metabolize pyruvate to acetyl-CoA, which can enter the citric acid cycle for complete oxidation to CO2 and HjO, linked to the formation of ATP in the process of oxidative phosphorylation (Figure 16-2). Glucose is the major fuel of most tissues. 

Figure 15-1. Outline of the pathways for the catabolism of dietary carbohydrate, protein, and fat. All the pathways lead to the production of acetyl-CoA, which is oxidized in the citric acid cycle, ultimately yielding ATP in the process of oxidative phosphorylation.

As with acetyl-CoA arising from glycolysis, it is oxidized to COj + HjO via the citric acid cycle. 

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