Pentose phosphate pathway impairment

Impairment of the Pentose Phosphate Pathway Leads to Erythrocyte Hemolysis... 

Many alcoholics such as Al Martini develop thiamine deficiency because alcohol inhibits the transport of thiamine through the intestinal mucosal cells. In the body, thiamine is converted to thiamine pyrophosphate (TPP). TPP acts as a coenzyme in the decarboxylation of a-keto acids such as pyruvate and a-ketoglutarate (see Fig. 8.11) and in the utilization of pentose phosphates in the pentose phosphate pathway. As a result of thiamine deficiency, the oxidation of a-keto acids is impaired. Dysfunction occurs in the central and peripheral nervous system, the cardiovascular system, and other organs. 

The cardiomyopathy is directly related to a reduction in the normal biochemical function of the vitamin thiamine in heart muscle. Inhibition of the a-keto acid dehydrogenase complexes causes accumulation of a-keto acids in heart muscle (and in blood), resulting in a chemically-induced cardiomyopathy. Impairment of two other functions of thiamine may also contribute to the cardiomyopathy. Thiamine pyrophosphate serves as the coenzyme for transketolase in the pentose phosphate pathway, and pentose phosphates accumulate in thiamine deficiency. In addition, thiamine triphosphate (a different coenzyme form) may function in Na conductance channels. 

Many of these deficiency conditions in animals can be explained in terms of the role of TPP in the oxidative decarboxylation of pyruvic acid. On a thiamin-deficient diet animals accumulate pyruvic acid and its reduction product lactic acid in their tissues, which leads to muscular weakness. Nerve cells are particularly dependent on the utilisation of carbohydrate and for this reason a deficiency of the vitamin has a particularly serious effect on nervous tissue. Since acetyl coenzyme A is an important metabolite in the synthesis of fatty acids (see p. 220), lipogenesis is reduced. The pentose phosphate pathway is also impaired by a deficiency of thiamin but there is little effect on the activity of the citric acid cycle. 

Because of the low activity of the pentose phosphate pathway in affected people, there is a lack of NADPH in red blood cells, and hence an impaired ability to remove hydrogen peroxide, which causes oxidative damage to the cell membrane lipids, leading to haemolysis. Other tissues are unaffected in favism because there are mitochondrial enzymes that can provide a supply of NADPH red blood cells have no mitochondria. 

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