PEPCKM

PEPCKM, or mitochondrial phosphoenolpyruvate carboxykinase, is an enzyme that catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, using GTP as a phosphate donor, within mitochondria. It is one of the two main mammalian forms of phosphoenolpyruvate carboxykinase, the other being the cytosolic enzyme PEPCK (PCK1).

In humans, PEPCK-M is encoded by the PCK2 gene and is localized to mitochondria. It contributes to gluconeogenic and anaplerotic flux in tissues where it is expressed. The enzyme’s mitochondrial location distinguishes its metabolic role from the cytosolic form, and its activity can influence the balance of intermediates available for energy production and biosynthesis.

Expression of PCK2 is tissue-dependent and responsive to metabolic state. PEPCK-M is widely expressed, with detectable levels in several organs, including kidney and pancreas, among others. Its activity supports mitochondrial production of phosphoenolpyruvate, which can feed into broader metabolic pathways and, in some contexts, influence glucose production and substrate utilization.

Regulation of PEPCK-M is linked to nutrient availability and energy status. During fasting or metabolic stress, PCK2 expression and activity may be modulated in certain tissues to adapt gluconeogenic and anabolic processes to the organism’s needs. The precise regulatory mechanisms can vary by tissue and condition.

Clinical and research interest in PEPCK-M centers on its role in metabolic diseases and cancer cell metabolism, where mitochondrial PEPCK activity can impact intermediate supply, redox balance, and energy homeostasis. PEPCK-M remains a focus of ongoing study to clarify its tissue-specific functions and potential as a therapeutic target.