Biological precursors of uric acid; the role of lactate, acetate, and formate in the synthesis of the ureide groups of uric acid.

Search for the biological sources of the ureide carbon atoms of uric acid has centered chiefly around compounds similar in structure to the ureide group of uric acid. One of the earliest studies on the precursors of uric acid was made by Wiener (3), who postulated that uric acid was formed by the condensation of 2 moles of urea with 1 of tartronic acid. Although this hypothesis was at first attractive, it has, however, been disproved as the mechanism of the biosynthesis of uric acid by several investigators using both in viva and in vitro techniques (4-10). Pyrimidines (11)) which are likewise related to purines, have also been excluded as precursors of uric acid, since they are oxidized almost quantitatively to urea by the mammal. More recent isotopic experiments of Plentl and Schoenheimer (12) also provide convincing evidence that pyrimidines do not participate in uric acid synthesis, A more serious difference of opinion, however, has persisted among investigators until recently concerning histidine and arginine as the precursors of purines or purine derivatives. The opening investigations on this subject were made by Ackroyd and Hopkins (13), who postulated that the imidazole nucleus of allantoin could be derived from either of these amino acids. Subsequent data obtained by comparing uric acid or allantoin excretion of animals fed diets high and low in these amino acids have not been altogether conclusive or in agreement (14-19). Results obtained by the isotope tracer technique, however, do not confirm the point of view that histidine or arginine may be precursors of uric acid (10). The feeding of N15-labeled ammonium citrate to rats and pigeons led to the incorporation of N15 into purines of the tissues and uric acid or allantoin of the excreta in much greater concentrations than in histidine or arginine of the tissue proteins. Moreover, uric acid isolated after the administration to the pigeon of arginine labeled with N15 did not contain significant amounts of N15 (20). These findings have led to the conclusion that the