IMP dehydrogenase, an enzyme linked with proliferation and malignancy

Abstract

PREVIOUS studies conducted in this laboratory demonstrated that in a spectrum of liver tumours with different growth rates there is an imbalance in the activities of key enzymes and competing pathways of carbohydrate, pyrimidine, DNA and ornithine metabolism1–4. Recent investigations on purine metabolism showed that in the hepatomas there was an increased capacity in the de novo pathway of biosynthesis of inosine 5′-monophosphate (IMP), as reflected in the increased activity of glutamine PRPP amidotransferase (EC 2.4.2.14) and a decrease in IMP catabolism5,6. These observations directed our attention to the metabolic fate of IMP because this purine nucleotide is at a strategic position in purine metabolism (Fig. 1). Control at such branching points is exerted primarily by modification of the activity or of the rate of synthesis of the first enzymes of the divergent pathways. In this instance, in normal conditions, a balance is maintained by both positive and negative feedback effects. Thus ATP is required for GMP biosynthesis and GTP for AMP biosynthesis; conversely, GMP and AMP each inhibit their own production7. In normal or malignant proliferation, or in response to a hormone stimulus, changes in control frequently involve reprogramming of gene expression. The theoretical framework and predictive value of generalisations about such biochemical changes (termed the molecular correlation concept) have been elaborated1–3.