Studies on the control of pyrimidine biosynthesis in human diploid cell strains, I. Effect of 6-azauridine on cellular phenotype.

Abstract

Hereditary orotic aciduria1' 2 is a rare recessive disease characterized by a megaloblastic anemia of infancy and severe developmental retardation.'-3Its clinical and hematologic features respond to supplementation of the diet with uridine.A The disorder is associated with deficient activity of two enzymes which catalyze sequential steps in the de novo biosynthesis of uridine-5'-monophosphate (UMP) (Fig. 1).The enzymes affected are orotidine-5'-monophosphate (OMP) pyrophosphorylase and OMP decarboxylase.46Two other enzymes of the path- way (Fig. 1), aspartate transcarbamylase4 and dihydroorotase (DHOase),2 3, 6 are not deficient.It is not yet known whether the gene affects dihydroorotic acid dehydrogenase.This report is one of a series describing the behavior of cultured diploid cell strains grown in the presence of substances which inhibit specific enzymes in the synthetic CARBAMYL PHOSPHATE ASPARTATE COOH HNH2 +ATP IH2 CONH2 GLUTAMINE ASPARTATE TRANSCARBAMYLASE COOH HeN CH2 f 1 2 DIHYDROOROTASE CO ,HH-COOH OROTIDINE -5'-MONOPHOSPHATE IOMP) OROTIC ACID FIG.1.-The de novo pathway of uridine-5'-monophosphate biosynthesis in mammalian cells.