PEPcarboxykinase

PEP carboxykinase (PEPCK) is a key gluconeogenic enzyme that converts oxaloacetate to phosphoenolpyruvate, linking the glycolytic and gluconeogenic pathways. The canonical reaction uses GTP as a phosphate donor: oxaloacetate + GTP -> phosphoenolpyruvate + GDP + CO2. In some prokaryotic and archaeal systems, ATP-dependent variants exist, but the GTP-dependent form is most common in animals and plants.

In mammals, there are two main gene products: PCK1, the cytosolic form, and PCK2, the mitochondrial form. PCK1 is highly expressed in liver and kidney and plays a central role in hepatic and renal gluconeogenesis, particularly during fasting or carbohydrate restriction. PCK2 is localized to mitochondria and also contributes to gluconeogenic flux, with activity that can influence metabolic signaling in various tissues.

Regulation of PEPCK activity is tightly tied to hormonal and nutritional state. Glucagon and cortisol stimulate transcription of PCK1 and PCK2, promoting glucose production during fasting, while insulin suppresses their expression. Nutrient status, energy charge, and transcriptional controls coordinate PEPCK levels to balance glucose output with energy needs.

PEP carboxykinase serves as a major control point for generating phosphoenolpyruvate, which is subsequently converted through a series of steps to glucose-6-phosphate and free glucose. It also helps integrate metabolic pathways that use non-carbohydrate precursors such as lactate, glycerol, and certain amino acids. Misregulation of PEPCK has been linked to metabolic disorders, including dysregulated gluconeogenesis in diabetes.

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