Control of purine biosynthesis de novo by orotic acid in vivo and in vitro

Abstract

The mechanism by which orotic acid decreases the concentration of adenine nucleotides in the livers of animals fed this pyrimidine precursor is presented. Orotic acid caused a marked inhibition of the incorporation of [1-14C]glycine into acid-soluble adenine nucleotides in the liver of albino rats in vivo and in vitro. This inhibition of the synthesis of adenine nucleotides in vitro was prevented by excess glutamine. The mechanism of the inhibition of biosynthesis of adenine nucleotides was attributable to an extensive depletion of pyrophosphorylribose 5-phosphate. This effect was not associated with a reduction of the activity of the enzymes responsible for the incorporation of glycine into purine. After the disappearance of orotic acid from the livers of animals previously fed a diet containing orotic acid, stimulation of the synthesis of adenine nucleotides was observed. This result appears to reflect a release of feedback inhibition of the biosynthetic pathway for purines by the reduced level of purine nucleotides and a compensatory increase in the synthesis of pyrophosphorylribose 5-phosphate. The studies suggest that the availability of pyrophosphorylribose 5-phosphate is a controlling factor in the biosynthesis of purine nucleotides de novo. © 1968.