CHAPTER 8 - Regulation of Purine and Pyrimidine Metabolism

Abstract

This chapter discusses the regulation of purine and pyrimidine metabolism. Biosynthesis de novo is the initial regulatory level to be considered in regulation of a variety of metabolic processes required to ensure optimal amounts and a balanced distribution of different forms of purine and pyrimidine classes. The first complete nucleotide to be formed in the purine biosynthetic pathway is inosine-5’-phosphate (IMP), and that in the pyrimidine pathway is uridine-5’-phosphate (UMP). The two pathways are operationally separate and distinct, and metabolically related only in that they share some common participants, such as glutamine, CO2, aspartate, and phosphoribosyl pyrophosphate. The major control of these biosynthetic pathways operates through end-product regulation, either by repression of enzyme synthesis at the level of gene expression, or by feedback inhibition of the activity of early enzymes. The end product of each of the pathways exerts negative control on itself, however, it may also act as a positive effector of the other pathway. Regulatory complications are introduced in both pathways by branch points from which the synthesis of other metabolites diverges. The pyrimidine pathway shares a common intermediate with the arginine pathway, and an intermediate in the purine pathway is also used for thiamine synthesis. After the synthesis of the first nucleotides, metabolic regulation must be directed toward the control of interconversions to yield the proper varieties and balance of the required nucleotide classes. The final consideration of regulation will deal with the mechanisms by which exogenously supplied aglycones and nucleosides are rescued and returned to the nucleotide pools.