Flux Control Coefficients of Glycinamide Ribonucleotide Transformylase for de novo Purine Biosynthesis

Abstract

The Pathway of de novo purine synthesis in mammals is initiated from phosphoribosylpyrophosphate and incorporates carbon and nitrogen from glutamine, glycine and the onecarbon pool to form initially IMP, from which the other purines can be synthesized. This pathway has been considered to be largely regulated by purines at the first enzyme, phosphoribosylpyrophosphate amidotransferase. In order for this enzyme to be an effective site of feedback regulation it must have a substantial flux control coefficient compared to the other enzymes in the de novo pathway. This feedback inhibitory mechanism results in significant control residing outside the purine de novo pathway, in purine utilization (positive control) and the alternative pathway of purine synthesis, purine salvage (negative control). As part of a continuing anti-tumour effort we are investigating specific steps in the de novo purine synthesis as targets for inhibition in cancer chemotherapy.