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Pyruvate Metabolism   

Pyruvate sits at an intersection of key pathways of energy metabolism. It is the end product of glycolysis and the starting point for gluconeogenesis, and can be generated by transamination of alanine. It can be converted by the pyruvate dehydrogenase complex to acetyl CoA which can enter the TCA cycle or serve as the starting point for the synthesis of long chain fatty acids, steroids, and ketone bodies. It also plays a central role in balancing the energy needs of various tissues in the body. Under conditions in which oxygen supply is limiting, (in exercising muscle) or in the absence of mitochondria, (in red blood cells), re-oxidation of NADH produced by glycolysis cannot be coupled to generation of ATP. Instead, its re-oxidation is coupled to the reduction of pyruvate to lactate. This lactate is released into the blood, and is taken up primarily by the liver, where it is oxidized to pyruvate and can be used for gluconeogenesis. Pyruvate participates in several key reactions and pathways. In glycolysis, phosphoenolpyruvate (PEP) is converted to pyruvate by pyruvate kinase. This reaction is strongly exergonic and irreversible. In gluconeogenesis pyruvate requires two enzymes, pyruvate carboxylase and PEP carboxykinase, to catalyze the reverse transformation of pyruvate to PEP. In fatty acid synthesis, pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA. In gluconeogenesis, the carboxylation by pyruvate carboxylase produces oxaloacetate. The fate of pyruvate depends on the cell energy charge. In cells or tissues with a high energy charge pyruvate is directed toward gluconeogenesis, but when the energy charge is low pyruvate is preferentially oxidized to CO2 and H2O in the TCA cycle, with generation of 15 equivalents of ATP per pyruvate. The enzymatic activities of the TCA cycle are located in the mitochondrion. When transported into the mitochondrion, pyruvate encounters two principal metabolizing enzymes: pyruvate carboxylase (a gluconeogenic enzyme) and pyruvate dehydrogenase (PDH). With a high cell-energy charge, acetyl-CoA, is able allosterically to activate pyruvate carboxylase, directing pyruvate toward gluconeogenesis. When the energy charge is low CoA is not acylated, pyruvate carboxylase is inactive, and pyruvate is preferentially metabolized via the PDH complex and the enzymes of the TCA cycle to CO2 and H2O.


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