Pyruvate thiamin deficiency

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). 

The answer is B. While all of the listed conditions are consistent with lethargy and developmental defects, the lactic acidosis rules out pyruvate kinase deficiency. Thiamine and niacin deficiencies are unlikely due to the lack of effect of vitamin supplementation. Excess pyruvate is the source of the elevated alanine in the serum. The clinical findings are thus consistent with pyruvate carboxylase deficiency, which is associated with severe hypoglycemia due to fasting due to impaired gluconeogenesis. 

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. ... 

Til. Role of the Vitamin Thiamine People with beriberi, a disease caused by thiamine deficiency, have elevated levels of blood pyruvate and a-ketoglutarate, especially after consuming a meal rich in glucose. How are these effects related to a deficiency of thiamine ... 

Diseases and disorders resulting from a deficiency of thiamine include beriben, opisthotonos (in birds), polyneuritis, hyperesthesia, bradycardia, and edema. Rather than a specific disease, beriberi may be described as a clinical state resulting from a thiamine deficiency. In body cells, thiamine pyrophosphate is required for removing carbon dioxide from various substances, including pyruvic acid. Actually, this is accomplished by a decarboxylase of which thiamine pyrophosphate is a part. Where... 

Thiamine Deficiency Individuals with a thiamine-deficient diet have relatively high levels of pyruvate in their blood. Explain this in biochemical terms. 

Answer Thiamine is required for the synthesis of thiamin pyrophosphate (TPP), a prosthetic group in the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes. A thiamin deficiency reduces the activity of these enzyme complexes and causes the observed accumulation of precursors. 

Thiamin-Responsive Pyruvate Dehydrogenase Deficiency Genetic deficiency of pyruvate dehydrogenase Ela (which is on the X chromosome) leads to potentially fatal lactic acidosis, with psychomotor retardation, central nervous system damage, atrophy of muscle fibers and ataxia, and developmental delay. At least some cases respond to the administration of high doses (20 to 3,000 mg per day) of thiamin. In those cases where the enzyme has been studied, there is a considerable increase in the of the enzyme for thiamin diphosphate. Female carriers of this X-linked disease are affected to a variable extent, depending on the X-chromosome inactivation pattern in different tissues (Robinson et al., 1996). 

Early studies showed that the development of neurological abnormalities in thiamin deficiency did not follow the same time course as the impairment of pyruvate and 2-oxoglutarate dehydrogenase or transketolase activities. The brain regions in which metabolic disturbances are most marked were not those that are vulnerable to anatomical lesions. These studies suggested a function for thiamin in the nervous system other than its coenzyme role. 

Pekovich SR, Martin PR and Singleton CK (1998) Thiamine deficiency decreases steady-state transketolase and pyruvate dehydrogenase but not alpha-ketoglutarate dehydrogenase mRNA levels in three human cell types. Journal of Nutrition 128, 683-7. 

Together with the fall in pyruvate dehydrogenase, there is a fall in the concentration of ATP in the heart, although the ATP ADP ratio in most tissues is not affected by thiamin deficiency (McCandless et cd., 1970). 

The impairment of pyruvate dehydrogenase in thiamin deficiency (Section... 

Thiamine deficiency results in inhibition of carbohydrate metabolism causing accumulation of Pyruvate. 

The severity of the symptoms of thiamin deficiency has been associated with energy intake. The consumption of large doses of glucose has been foimd to induce an unusual rise in plasma pyruvate and lactate, as well as neurological symptoms, in thiamin deficient humans. Because of this association, the thiamin requirement is sometimes expressed on a per energy intake basis. 

Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y et al. Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Biochim Biophys Acta 2002 1588 79-84. 

Thiamine deficiency causes decreased pyruvate oxidation, leading to accumulation of pyruvate and lactate, particularly in the blood and brain, and is accompanied by impairment of the cardiovascular, nervous, and gastrointestinal systems (Chapter 38). Inherited deficiency of pyruvate dehydrogenase complex is accompanied by lactic acidemia and abnormalities of the nervous system (e.g., ataxia and psychomotor retardation). Pyruvate carboxylase deficiency causes similar abnormalities (Chapter 15). Both inherited disorders of pyruvate utilization are autosomal recessive. 

Thiamine deficiency can be assessed by measuring blood levels. Increased blood levels of pyruvate and lactate suggest thiamine deficiency. Measurement of erythrocyte transketolase activity, which requires TPP as a coenzyme, confirms the deficiency. 

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