What Is the Metabolic Role of Phosphoenolpyruvate Carboxykinase

The enzyme phosphoenolpyruvate carboxykinase (GTP; EC 4.1.1.32) (PEPCK)2 has the unusual distinction of being very well studied but metabolically misunderstood. As we will document in this minireview, the enzyme has been almost exclusively linked to gluconeogenesis to the point that changes in the levels of PEPCK mRNA or its activity are associated with the control of hepatic glucose output and, more recently, with alterations in life span. That a tissue such as brown adipose tissue, which does not make glucose, has more PEPCK activity on a protein basis than is present in the liver is largely ignored. In addition, all eukaryotes have a gene for both a mitochondrial (PEPCK-M) and cytosolic (PEPCK-C) form of the enzyme. In the livers of most mammals studied to date (including humans), 50% of the total PEPCK activity is PEPCK-M. However, for reasons to be discussed, only PEPCK-C has been studied in any detail in mammals. Thus, the “strange case of PEPCK-M” deserves our attention. This minireview is an attempt to broaden our prospective on the metabolic role of this enzyme by reviewing the body of literature that has accumulated demonstrating that PEPCK plays a key role in a several metabolic processes associated with cataplerosis.