Carbohydrates pyruvic acid oxidation

Finally, perhaps an explanation for the beneficial effects of coenzyme A (CoA), malate and pyruvate for the extracellular in vitro growth of P. lophurae found by Trager (1952) and interpreted by Moulder (1962) to neatly explain the shift in pattern of carbohydrate metabolism accompanying liberation of parasites from the host cell. .. (The) lack of CoA in free parasites logically explains the lessened rate of pyruvic acid oxidation via the Krebs cycle. It is difficult to escape the conclusion that the inability of plasmodia to synthesize CoA extracellularly results in extensive dislocations in glucose metabolism, which in turn contribute heavily to the restriction of the malarial parasite to an intracellular habitat is this malate and pyruvate could be linked to the generation of dihydronicotinamide adenine dinucleotide (NADH) for glycolysis, and a CoA deficiency could limit activity in pathways other than the TCA cycle. 

Besides Szent-Gyorgi and Krebs, other groups were attacking the problem of carbohydrate oxidation. Weil-Malherbe suggested It is probable that the further oxidation of succinic acids passes through the stages of fumaric, malic, and oxaloacetic acid pyruvic acid is formed by the decarboxylation of the latter and the oxidative cycle starts again. K.A.C. Elliott, from the Cancer Research Laboratories at the University of Pennsylvania, also proposed a cycle via some 6C acid. 

The tricarboxylic acid cycle was therefore validated, having been tested not only in pigeon-breast muscle but also with brain, testis, liver, and kidney. The nature of the carbohydrate fragment entering the cycle was still uncertain. The possibility that pyruvate and oxaloacetate condensed to give a 7C derivative which would be decarboxy-lated to citrate, was dismissed partly because the postulated compound was oxidized at a very low rate. Further, work on the oxidation of fatty acids (see Chapter 7) had already established that a 2C fragment like acetate was produced by fatty acid oxidation, en route for carbon dioxide and water. It therefore seemed likely that a similar 2C compound might arise by decarboxylation of pyruvate, and thus condense with oxaloacetate. For some considerable time articles and textbooks referred to this unknown 2C compound as active acetate. ... 

The source of ACCOA for citrate synthase (reaction 2) is the oxidation of carbohydrate, fatty acid, and amino acid molecules. The COAS generated by citrate synthase is used in the oxidation of substrates (such as pyruvate via pyruvate... 

The formation of acetyl CoA from carbohydrates is less direct than from fat. Recall that carbohydrates, most notably glucose, are processed by glycolysis into pyruvate (Chapter 16). Under anaerobic conditions, the pyruvate is converted into lactic acid or ethanol, depending on the organism. Under aerobic conditions, the pyruvate is transported into mitochondria in exchange for OH by the pyruvate carrier, an antiporter (Section 13.4). In the mitochondrial matrix, pyruvate is oxidatively decarboxylated by the pyruvate dehydrogenase complex to form acetyl CoA. 

The acetyl CoA formed in fatty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation are appropriately balanced. The reason is that the entry of acetyl CoA into the citric acid cycle depends on the availability of oxaloacetate for the formation of citrate, but the concentration of oxaloacetate is lowered if carbohydrate is unavailable or improperly utilized. Recall that oxaloacetate is normally formed from pyruvate, the product of glycolysis, by pyruvate carboxylase (Section 16.3.1). This is the molecular basis of the adage that fats burn in the flame of carbohydrates. 

Carbohydrates are introduced into the Krebs cycle at the point where pyruvate dehydrogenase catalyzes conversion of pyruvate to acetyl-Co A with the concomitant reduction of NAD. Citrate synthase catalyzes introduction of the 2-carbon unit of acetyl-CoA into the Krebs cycle. Pyruvate can arise from glucose, fructose, lactate, alanine, and glycerol. Acetyl-CcjAcan arise from pyruvate, as well as from fatty acids. Oxidation of fatty acids results in production of acetyl-Co A, which enters the Krebs cycle at the point catalyzed by citrate synthase. Breakdown of ketogenic amino adds also results in the production of acctyl-CoA, which enters the Krebs cycle at this point. Citrate and malate occur in high cor centrations in certain fruits and vegetables. These chemicals directly enter the Krebs cycle at the indicated points. 

TCA cycle. (tricarboxylic acid cycle Krebs cycle citric acid cycle). A series of enzymatic reactions occurring in living cells of aerobic organisms, the net result of which is the conversion of pyruvic acid, formed by anaerobic metabolism of carbohydrates, into carbon dioxide and water. The metabolic intermediates are degraded by a combination of decarboxylation and dehydrogenation. It is the major terminal pathway of oxidation in animal, bacterial, and plant cells. Recent research indicates that the TCA cycle may have predated life on earth and may have provided the pathway for formation of amino acids. 

Acetyl CoA serves as a common point of convergence for the major pathways of fuel oxidation. It is generated directly from the (3-oxidation of fatty acids and degradation of the ketone bodies (3-hydroxybutyrate and acetoacetate (Fig. 20.14). It is also formed from acetate, which can arise from the diet or from ethanol oxidation. Glucose and other carbohydrates enter glycolysis, a pathway common to all cells, and are oxidized to pyruvate. The amino acids alanine and serine are also converted to pyruvate. Pyruvate is oxidized to acetyl CoA by the pyruvate dehydrogenase complex. A number of amino acids, such as leucine and isoleucine are also oxidized to acetyl CoA. Thus, the final oxidation of acetyl CoA to CO2 in the TCA cycle is the last step in all the major pathways of fuel oxidation. 

ANAEROBIC CARBOHYDRATE METABOLISM Yeasts growing in media containing high concentrations of fermentable carbohydrate invariably metabolize it fermentatively to produce ethanol and CO2. If air is present, and when the sugar concentration has been lowered, the ethanol is respired using the metabolic routes described above. Under the anaerobic conditions of a brewery fermentation the hexoses derived from wort fermentable carbohydrates are catabolized by the EMP pathway (Fig. 17.2) to pyruvic acid. The pyruvate produced is decarboxylated by the enzyme pyruvate decarboxylase, with the formation of acetaldehyde and CO2. The enzyme requires the cofactor thiamine pyrophosphate (TPP) for activity and the reaction is shown in Fig. 17.10. The acetaldehyde formed acts (in the absence of the respiratory chain) as an electron acceptor and is used to oxidize NADH with the formation of ethanol ... 

WE HAVE NOW studied the structures and typical reactions of the major types of organic functional groups. Further, we have examined the structures of carbohydrates, amino acids and proteins, nucleic acids, and lipids. Now let us apply this background to the study of the organic chemistry of metabolism. In this chapter, we study three key metabolic pathways glycolysis, the citric acid cycle, and the /3-oxidation of fatty acids. The first is a pathway by which glucose is converted to pyruvate and then to acetyl coenzyme A. The second is a pathway by which the hydrocarbon chains of fatty acids are degraded, two carbons at a time, to acetyl coenzyme A. The third is the pathway by which the carbon skeletons of carbohydrates, fatty acids, and proteins are oxidized to carbon dioxide. 

The reaction that uses most of the acetyl-CoA formed by pyruvic acid is the condensation of acetic acid and the keto form of oxaloacetic acid to yield citric acid by forming a carbon-to-carbon bond between the methyl carbon of acetyl-CoA and the carbonyl carbon of oxaloacetate. This reaction is interesting in more than one respect. In addition to the fact that the reaction introduces the oxidation product of fatty acids, carbohydrates, and proteins into the tricarboxylic cycle by converting the 4-carbon chain of oxaloacetic acid into a 6-carbon chain (citric acid), the condensing enzyme presents a fascinating stereospecificity. 

Many of these deficiency conditions in animals can be explained in terms of the role of TPP in the oxidative decarboxylation of pyruvic acid. On a thiamin-deficient diet animals accumulate pyruvic acid and its reduction product lactic acid in their tissues, which leads to muscular weakness. Nerve cells are particularly dependent on the utilisation of carbohydrate and for this reason a deficiency of the vitamin has a particularly serious effect on nervous tissue. Since acetyl coenzyme A is an important metabolite in the synthesis of fatty acids (see p. 220), lipogenesis is reduced. The pentose phosphate pathway is also impaired by a deficiency of thiamin but there is little effect on the activity of the citric acid cycle. 

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