Pyruvate accumulation

From all the hypotheses mentioned above, the low flux of pyruvate into the TCA cycle is better explained by a decreased activity of several enzymes pyruvate carboxylase, pyruvate phosphoenol carboxykinase, pyruvate dehydrogenase, and malic enzyme II (Figure 4.3). Then, the pyruvate accumulated is converted to lactate by the enhanced catalytic action of the lactate dehydrogenase, as an alternative pathway to generate energy for cellular processes. 

Fig. 7. Branch point between fermentation and respiration. At low pyruvate flux, the low of the Pdh complex for pyruvate results in oxidative decarboxylation to form acetyl CoA and NADH. The acetyl CoA can then can go into energy generation (via respiration) or fatty acid synthesis. At high glycolytic flux, pyruvate accumulates, and the higher of Pdc favors acetaldehyde formation and ethanol production. Accumulation of acetate can interfere with mitochondrial function. Pyk Pyruvate kinase Pdh pyruvate dehydrogenase Pdc pyruvate decarboxylase Aid (Dha) aldehyde dehydrogenase Adh alcohol dehydrogenase Acs acetyl CoA synthetase. (Taken from Postma et al. [169])...

A number of workers have shown that these acids accumulate in the blood during liver failure after administration of these acids themselves or of their metabolic precursors. After a glucose load, for instance, pyruvate accumulates in the blood of such patients, the increase in pyruvate concentration being higher and more lasting than in normal subjects (A5, G5). 

Roughan etal 2) compared acetate, pyruvate and malonate as potential precursors and found that acetate was about three times better than pyruvate while malonate was not used at all. Consistent with this result is the report of Kuhn elal Q) who found that acetate concentration in plant tissue is in the order of mM and that acetate thiokinase is localized in the plastld. Nevertheless, alternative substrates can not be entirely excluded at this stage. Schulze-Siebert etal (4) have reported that when chloroplasts are incubated with bicarbonate, pyruvate accumulates in the chloroplast. Furthermore Williams and Randall (5) have reported that pyruvate dehydrogenase of pea chloroplasts has an activity of 6-9 pmol/h/mg chlorophyll. It is therefore conceivable that the acetyl CoA used in the first steps of fatty acid synthesis is derived from pyruvate. 

The excessive pyruvate accumulation might be due to the coincident measurement of alpha-keto glutaric acid when the nonchromatographio techniques are used this is perhaps the case in the psychotic patients, at least since we observed a rise in alpha-keto-glutaric acid rather than the normal fall after glucose by mouth. 

In thiamine deficiency, pyruvate accumulates in the blood and tissues and there is a change in the lactate-pyruvate ratio. These findings have been used in detecting thiamine deficiency in man. MIorwitt has proposed as a test of thiamine nutrition the simultaneous measurement of lactic acid, pyruvic acid, and glucose in the blood 5 min. after mild exercise and 60 min. after ingestion of glucose. The carbohydate index (C.I.) is determined from the formula... 

In the pigeon, opisthotonos is the major neurological symptom of thiamine deficiency. Pyruvate utilization is impaired by lack of cocarboxylase ( = thiamine pyrophosphate). Oxygen consumption of nerve cells decreases since these cells obtain the greatest part of their energy from carbohydrate metabolism. Pyruvate accumulates in the tissues. In a few minutes, after addition of thiamine to the systems in vitro, the O2 consumption increases. Similarly the opisthotonos disappears 1 hr after intracerebral injection of thiamine. 

The first step of this reaction, decarboxylation of pyruvate and transfer of the acetyl group to lipoic acid, depends on accumulation of negative charge on the carbonyl carbon of pyruvate. This is facilitated by the quaternary nitrogen on the thiazolium group of thiamine pyrophosphate. As shown in (c), this cationic... 

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in isovaleric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated... 

An especially cogent argument for the acetaldehyde theory is the fact that considerable amounts of pyruvic acid accumulate in the organism... 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Straightforward thiamine deficiency in man, beri-beri, is characterized by accumulation of pyruvic and lactic acids in the blood and brain, and impairment of cardiovascular, nervous, and gastrointestinal function (DIO, G17, P4, Yl). Neurological lesions characterize thiamine deficiency in growing rats (B40), guinea pigs (M6), mice (M13), chicks, and pigeons (B30). The effects of thiamine deficiency on the central nervous system of animals have been reviewed (DIO). 

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