Pyruvic acid oxidation

The clinical significance of thiamine and its necessity for pyruvic acid oxidation has been discussed. Recent reports concerning the coenzyme function of thiamine in pentose (H13), tryptophan (D2), and lipoic acid metabolism (R6) have increased our knowledge of thiamine in metabolism and lend added interest to the role of thiamine in clinical problems. This method has also been used to assay thiamine in liver and brain. 

During strenous exercise there is little oxygen, 02, available for muscle cells. Under these conditions, the muscle cells derive most of their energy from the anaerobic conversion of pyruvic acid, C3H403, into lactic acid, C3H603. The buildup of lactic acid makes the muscles ache and fatigue quickly. Is the pyruvic acid oxidized or reduced as it transforms into lactic acid ... 

Lipmann, F. An analysis of the pyruvic acid oxidation system. Cold Spring Harbor Symposium Quant. Biol. 7, 248—259 (1939). 

The bulk of the energy demands of the cell are met within the mitochondria by the production of ATP during the oxidation of substrates by way of the hydrogen transport line (see Chapter 7). When the enzymes and carriers of this system are studied in isolation, they are found to be capable of extremely rapid reactions, yet if the intact mitochondrion is presented with substrates such as pyruvic acid it is found that the rate of pyruvic acid oxidation reaches a maximum which is considerably below the maximum velocities shown by the individual carriers. As increasing the amount of pyruvic acid does not alter this oxidation rate, it is clear that the mitochondrion must contain its own built-in control system to limit the rate at which it burns fuel. We can isolate some of the elements in this control system if we draw a schematic flowsheet of the operations involved in oxidation (Figure 25). 

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. 

The reactions in which pyruvic acid is oxidized to form CO2 and acetic acid are of the greatest significance since they constitute the link between glycolysis and the Krebs cycle. These reactions involve a considerable number of coenzymes thiamine pyrophosphate, lipoic acid, Co A, and NAD. Much of our knowledge of pyruvic acid oxidation depended on the discovery of CoA and lipoic acid, and it might be useful to review the biochemistry of lipoic acid before we enter into more detail. Refer to the chapter on vitamins for a review of the metabolism and catabolism of thiamine, CoA, and NAD. 

Pyruvic decarboxylase controls the entry of the end products of glycolysis into the Krebs cycle. Therefore, thiamine deficiency must have dramatic consequences if no alternative pathway is available for pyruvic acid oxidation. Understandably, in the absence of an alternative pathway, thiamine deficiency leads to a block of pyruvic decarboxylation, which is the first of the two reactions of the Krebs cycle requiring thiamine. In addition, half of the thiamine content of the brain is used in that reaction. The maintenance of the integrity of the Krebs cycle is probably more important to the cell than that of the hexose monophosphate shunt. 

IS the oxidation of lactic acid to pyruvic acid by NAD and the enzyme lactic acid coenzyme NAD ... 

Methylsuccinic acid has been prepared by the pyrolysis of tartaric acid from 1,2-dibromopropane or allyl halides by the action of potassium cyanide followed by hydrolysis by reduction of itaconic, citraconic, and mesaconic acids by hydrolysis of ketovalerolactonecarboxylic acid by decarboxylation of 1,1,2-propane tricarboxylic acid by oxidation of /3-methylcyclo-hexanone by fusion of gamboge with alkali by hydrog. nation and condensation of sodium lactate over nickel oxide from acetoacetic ester by successive alkylation with a methyl halide and a monohaloacetic ester by hydrolysis of oi-methyl-o -oxalosuccinic ester or a-methyl-a -acetosuccinic ester by action of hot, concentrated potassium hydroxide upon methyl-succinaldehyde dioxime from the ammonium salt of a-methyl-butyric acid by oxidation with. hydrogen peroxide from /9-methyllevulinic acid by oxidation with dilute nitric acid or hypobromite from /J-methyladipic acid and from the decomposition products of glyceric acid and pyruvic acid. The method described above is a modification of that of Higginbotham and Lapworth. ... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

FIGURE 25.1 The citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents (electrons) for fatty acid synthesis. The shuttle collects carbon substrates, primarily from glycolysis but also from fatty acid oxidation and amino acid catabolism. Most of the reducing equivalents are glycolytic in origin. Pathways that provide carbon for fatty acid synthesis are shown in blue pathways that supply electrons for fatty acid synthesis are shown in red. 

Write a balanced equation for the oxidation of pyruvic acid to CC and H20. 

Let us look at a very simple part of the overall process. The first thing that happens is the breakdown of pyruvic acid into acetic acid and CO (the oxidation process has started ) ... 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

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