Pyrimidine overproduction in lower organisms

Abstract

During rapid growth, the excretion of pyrimidines, predominantly uracil, is a common characteristic of both procaryotic and eucaryotic cells. In Escherichia coli there are some K12 strains which excrete orotic acid (OA) and not uracil. This is caused by mutation in the pyrF gene. This allele does not affect the growth rate in the absence of uracil. Other E. coli (both K12 and B strains) excrete uracil. Exogenous uracil does not completely inhibit or repress the de novo enzymes, since high levels of uracil only decrease OA excretion by about fifty percent. The exogenous uracil is converted to UMP in these cells as is shown by their increased sensitivity to pyrimidine analogues. Excretion of OA by some strains and uracil excretion by others explain the significance of heretofore confusing data such as differential ???ü?C-uracil labeling of RNA, difficulties in isolating uracil auxotrophs using penicillin, and the derepression of the de novo synthesis of wild type enzymes. Because excretion of uracil and OA presents an apparently inefficient step in the otherwise highly regulated pyrimidine biosynthesis, this phenomenon must be explained. Since a uridine compound is a corepressor in PRPP biogenesis, one must wonder whether or not a "well-turned" cell could survive if PRPP levels were a function of a molecule which was allowed to fluctuate wildly with exogenous sources. Rather, a selective advantage is conferred on the cell by the enzymes uridine kinase and uridine phosphorylase which prevent exorbitantly high UMP pools causing high UDP and UTP pools. For these would undoubtedly cause PRPP starvation and thus prevent either protein synthesis and/or nucleic acid synthesis.