Oxoglutarate thiamin deficiency

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. 

ThDP plays a crucial role as coenzyme for several enzymes and enzyme complexes such as transketolase (EC 2.2.1.1) and the enzyme complexes pyruvate (EC 1.2.4.1) and 2-oxoglutarate (EC 1.2.4.2) dehydrogenases, present in nearly all organisms. They play important catabolic roles and are key actors in cell energy metabolism (Figure 5.1). Reduced activity of these enzymes as a consequence of thiamin deficiency results in decreased glucose oxidation. As the brain heavily relies on oxidative metabolism, it is more severely affected by thiamin deficiency than other organs. 

In thiamine deficiency, therefore, the formation from pyruvate of acetyl-coenzyme A, which is normally followed by the oxidation of the 2-C acetyl fragment to CO2 and H2O via the citric acid cycle is blocked, and the pyruvate formed by glycolysis consequently accumulates. In addition in its role in the oxidative decarboxylation of pyruvate, thiamine pyrophosphate is also needed as a co-enzyme in the similar decarboxylation of the closely related a-oxoglutarate, one of the intermediaries in the citric acid cycle. 

Deficient activity of both pyruvate and 2-oxoglutarate dehydrogenase complexes has also been reported in three infant siblings, with pyruvic, lactic and 2-oxoglutaric aciduria, fasting hypoglycaemia and a fatal course in two of the siblings despite attempts at treatment with thiamin, iipoate, biotin. 

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