Phosphoenolpyruvate carboxykinase: a prospective on its biological role 50 years after its discovery

Abstract

Phosphoenolpyruvate carboxykinase (PEPCK) was discovered 50 years ago by Kiyoshi Kurahashi and Merton F. Utter. There are two forms of the enzyme, a cytosolic (PEPCK-C) and a mitochondrial (PEPCK-M) form, which are coded for by different nuclear genes; species vary in the relative levels of the enzyme present in their tissues. Over the years PEPCK has been largely associated with gluconeogenesis, although it is present in tissues that do not make glucose (i.e. white and brown adipose tissue, small intestine, lung, mammary gland during lactation and muscle). Most references to PEPCK today are to PEPCK-C, largely because it is present in high activity in rodent species and the gene is remarkably responsive to hormones and to dietary and developmental stimuli; its transcription is markedly induced in the liver during diabetes, contributing to an elevated hepatic glucose output. Recent studies have suggested that PEPCK has a wider metabolic role. It has been implicated in glyceroneogenesis in adipose tissue, liver and muscle and in cataplerosis in the liver. The deletion of the gene for PEPCK-C in the liver results in a fatty liver, while the ablation of its expression in white adipose tissue causes lipodsytrophy and over expression in that tissue leads to obesity. Over expression of the gene for PEPCK-C in mouse muscle greatly enhances the capacity of the animals to run. This lecture will review the metabolic function of both isoforms of PEPCK, drawing on over 50 years of research on the enzyme and will emphasize an emerging view that PEPCK is critical for both carbohydrate and lipid metabolism and in controlling citric acid cycle flux. Supported by DK25541 from the NIH.