Phosphoenolpyruvate carboxykinase 1 (PCK1) (PCK1)

Phosphoenolpyruvate carboxykinase 1 (PCK1), also known as PEPCK-C, is a rate-limiting enzyme in the gluconeogenesis pathway that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the cytosol. This metabolic step is critical for the maintenance of blood glucose levels during fasting and is primarily regulated by hormonal signals such as glucagon, glucocorticoids, and insulin (UniProt P35558). In metabolic diseases like Type 2 diabetes, PCK1 is often overexpressed, leading to excessive hepatic glucose production and hyperglycemia (PubMed: 29453285). Beyond its role in glucose synthesis, PCK1 is involved in glyceroneogenesis and the regulation of the TCA cycle, making it a central node in cellular metabolism. While direct clinical inhibitors of PCK1 are not yet standard therapy, many anti-diabetic drugs like metformin and thiazolidinediones exert their effects partly by downregulating PCK1 expression or activity (PubMed: 11724330). Recent research also highlights its role in cancer metabolism, where it can support tumor growth by providing biosynthetic intermediates (PubMed: 31064772).

Other names

PEPCK-CPEPCK1Phosphoenolpyruvate carboxylaseCytosolic phosphoenolpyruvate carboxykinase

Inhibition of the rate-limiting step of gluconeogenesis by preventing the conversion of oxaloacetate to phosphoenolpyruvate; indirect downregulation via AMPK activation or PPAR-gamma modulation.