Oxidation pyruvate

Several mechanisms of fialuridine-induced hepatotoxicity have been suggested fialuridine and its metabolites inhibit mitochondrial DNA replication, leading to decreased mitochondrial DNA and mitochondrial ultrastructural defects [61]. Another mechanism suggested lies in pyruvate oxidation inhibition [62]. 

Fluoroethanol itself is innocuous towards a variety of tissue constituents, a series of enzymes in rat-liver mince, and the respiration and metabolism in liver, kidney, heart and brain slice.3 After a period of incubation in those tissues known to contain alcohol dehydrogenase, e.g. liver and kidney, the respiration and pyruvate oxidation were strongly inhibited. Likewise, following a period of incubation with yeast, acetate oxidation was blocked. These inhibitions were similar to those produced by fluoroacetate, and the facts can best be explained by the oxidation of fluoroethanol to fluoroacetic acid by alcohol dehydrogenase. 

TAs one might predict, mutations in the genes for the subunits of the PDH complex, or a dietaiy thiamine deficiency, can have severe consequences. Thiamine-deficient animals are unable to oxidize pyruvate normally. This is of particular importance to the brain, which usually obtains all its energy from the aerobic oxidation of glucose in a pathway that necessarily includes the oxidation of pyruvate. Beriberi, a disease that results from thiamine deficiency, is characterized by loss of neural function. This disease occurs primarily in populations that rely on a diet consisting mainly of white (polished) rice, which lacks the hulls in which most of the thiamine of rice is found. People who habitually consume large amounts of alcohol can also develop thiamine deficiency, because much of their dietaiy intake consists of the vitamin-free empty calories of distilled spirits. An elevated level of pyruvate in the blood is often an indicator of defects in pyruvate oxidation due to one of these causes. ... 

The PDH complex of mammals is strongly inhibited by ATP and by acetyl-CoA and NADH, the products of the reaction catalyzed by the complex (Fig. 16-18). The allosteric inhibition of pyruvate oxidation is greatly enhanced when long-chain fatty acids are available. AMP, CoA, and NAD+, all of which accumulate when too little acetate flows into the citric acid cycle, allosterically activate the PDH complex. Thus, this enzyme activity is turned off when ample fuel is available in the form... 

Pyruvate oxidation (two per glucose) 2 NADH (mitochondrial matrix) 5... 

The isolation of lipoic acid in 1951 followed an earlier discovery that the ciliate protozoan Tetrahymena geleii required an unknown factor for growth. In independent experiments acetic acid was observed to promote rapid growth of Lactobacillus casei, but it could be replaced by an unknown "acetate replacing factor." Another lactic acid bacterium Streptococcus faecalis was unable to oxidize pyruvate without addition of "pyruvate oxidation factor." By 1949, all three unknown substances were recognized as identical.291 2913 After working up the equivalent of 10 tons of water-soluble residue from liver, Lester Reed and his collaborators isolated 30 mg of a fat-soluble acidic material which was named lipoic acid (or 6-thioctic acid).292 294... 

Acetyl-CoA is the only compound that can enter the TCA cycle when the cycle is operating purely oxidatively, but one molecule of oxaloacetate must enter for each molecule of citrate, a-ketoglutarate, or succinyl-CoA that is removed for use in biosynthesis. It follows that pyruvate is a major metabolic branchpoint in a cell that is living on carbohydrate. The partitioning of pyruvate between decarboxylation to acetyl-CoA and carboxylation to oxaloacetate is, in effect, partitioning between the two major metabolic uses of pyruvate oxidation of carbon for regeneration of ATP and conversion to starting materials for biosynthesis. 

Gunsalus, I. C. The chemistry and function of the pyruvate oxidation factor (lipoic acid). J. Cellular Comp. Physiol. 41, Suppl. 1, 113—136 (1953). 

Stern, J. R. Role of cofactors in pyruvate oxidation and synthesis by extracts of Clostridium kluyveri. In Non-Heme Iron Proteins Role in Energy Conversion, A. San Pietro, ed., Antioch Press, Yellow Springs, Ohio, pp. 199—210 (1965). 

The GTP formed as described above yields ATP [via nucleoside diphosphokinase]. The reduced coenzymes (4 NADH and FADH2) feed electrons into the mitochondrial electron transport chain (ETC) to yield 14 ATP per pyruvate oxidized (12 ATP/4 NADH and 2 ATP/FADH2) through the process of oxidative phosphorylation as described in Section 13.5. This total yield of ATP corresponds to a total of 32 ATP per glucose oxidized plus a further 6 ATP from mitochondrial oxidation of NADH generated in glycolysis, that is, 38 ATP per glucose oxidized. 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

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