Phosphoenolpyruvate carboxykinase revisited: Insights into its metabolic role

Our understanding of the major metabolic pathways is built on a solid record of research extending back to the beginnings of biochemistry. It is unlikely, for example, that a new pathway for the utilization of major metabolic fuels will be described in mammals. What is less certain, however, are the mechanisms responsible for the regulation of the complex networks of enzymatic reactions that make up a metabolic pathway. As an example, the details of the interaction between fatty acid and carbohydrate metabolism remain to be fully clarified. However, new insights have changed the way we view key steps in metabolic pathways. As we shall develop in this article, enzymes once considered important for one metabolic pathway are now being shown to be critical for another. This is primarily because of advances made in molecular genetics and in vivo tracer methods over the past three decades that have provided a new set of tools for the study of metabolism. The result has greatly extended our understanding of the role played by individual enzymes in specific metabolic pathways. In this review we will present the latest information on the biological role of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) in intermediary metabolism. Since its discovery in the late 1950s, PEPCK has been recognized as a key step in hepatic and renal gluconeogenesis. It is widely recognized as a critical enzyme in diabetes, because an elevation in its activity is associated with the increased rate of hepatic glucose output characteristic of that disease [1]. The regulation of transcription of the gene for the cytosolic form of PEPCK (PEPCK-C) has also been intensively studied and will be detailed in a second article in this series. The interaction of transcription factors that control the expression of the gene for PEPCK-C has been something of a model for understanding the complex mechanisms responsible for regulating transcription of an acutely controlled gene that is responsive to a wide variety of metabolically generated signals.

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