PCK1

PCK1, or phosphoenolpyruvate carboxykinase 1, encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). This enzyme catalyzes the GTP-dependent conversion of oxaloacetate to phosphoenolpyruvate in the cytosol, a rate-limiting step in gluconeogenesis and a branch pathway called glyceroneogenesis that provides glycerol-3-phosphate for triglyceride synthesis.

Expression of PCK1 is highest in liver and kidney, with notable activity in adipose tissue during lipolysis; it is generally low in most other tissues.

Regulation of PCK1 involves hormonal signals and nutrient status. Glucagon and cortisol activate PCK1 expression via the cAMP/PKA signaling pathway and transcription factors such as CREB, FOXO1, and PGC-1alpha, while insulin suppresses expression. Nutrient and energy status also influence PCK1 through transcriptional and post-translational mechanisms, reflecting the enzyme’s role in maintaining glucose and lipid homeostasis.

Clinical and research notes on PCK1 emphasize its role in endogenous glucose production. Hepatic PCK1 activity is often upregulated in insulin resistance and type 2 diabetes, contributing to hyperglycemia, and pharmacological inhibition of PCK1 has been explored as a strategy to reduce hepatic glucose output. In animal models, Pck1 deficiency reduces gluconeogenesis but can trigger compensatory metabolic adaptations, underscoring the enzyme’s integrated role in energy metabolism.

Gene family context places PCK1 among two mammalian phosphoenolpyruvate carboxykinases: the cytosolic PCK1 and the mitochondrial PCK2. PCK2 localizes to mitochondria and contributes to gluconeogenesis from within that organelle. The two enzymes are evolutionarily conserved with tissue-specific expression patterns across vertebrates.