PEPCKC

PEPCK-C, or phosphoenolpyruvate carboxykinase, cytosolic form, is a cytosolic enzyme that plays a central role in gluconeogenesis, the production of glucose from non-carbohydrate precursors. It catalyzes the GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, providing a critical branch point that links amino acid and glycerol inputs to glucose formation. The reaction also contributes to glyceroneogenesis in adipose tissue, helping to generate glycerol-3-phosphate for triglyceride synthesis.

In humans, the cytosolic isoform is encoded by the PCK1 gene, while the mitochondrial isoform is encoded by PCK2. PEPCK-C is expressed mainly in liver, kidney, and adipose tissue, with activity increasing during fasting. Regulation is complex and influenced by hormonal signals such as glucagon and cortisol (which stimulate transcription) and insulin (which suppresses expression). Transcription factors including CREB, FoxO1, and C/EBP family members contribute to its hormonal control.

Physiologically, PEPCK-C supports hepatic and renal glucose production during prolonged fasting and participates in lipid metabolism via glyceroneogenesis. Dysregulation of hepatic PEPCK-C is associated with altered glucose homeostasis in metabolic disease, notably the upregulation of gluconeogenesis in type 2 diabetes.

In research, altering PEPCK-C levels in animal models has produced varied metabolic phenotypes, including changes in energy expenditure and adiposity in some mice; these findings are context-dependent and not yet directly translatable to humans.

See also: PCK1 gene, PCK2 gene, gluconeogenesis.