A Study of the Metabolism of Dietary Hypoxan- Thine and Xanthine in the Rat*

It was previously reported (1) that dietary adenine is utilized by the rat as a precursor of both the adenine and the guanine of nucleic acids. Although several compounds containing 1 to 3 carbons have been shown to be incorporated into uric acid (2, 3) or guanine (4), none of the more complex precursors of the purine ring has been identified. The postulation that the immediate metabolic precursor of adenine is the corresponding oxygen analogue, hypoxanthine, is supported by several lines of evidence. The demonstration by Krebs et al. (5, 6) that pigeon liver slices synthesize hypoxanthine led him to suggest that it is an intermediate in the formation of uric acid in the pigeon. Sonne, Buchanan, and Delluva (2) have pointed out that their results are in accord with Krebs’ hypothesis. Greenberg (7) has demonstrated that formic acid, which is a precursor of uric acid in the intact animal (2), is also incorporated into the hypoxanthine produced in pigeon liver homogenates. In the case of Neurospora crassa, forty-five adenine-requiring mutants have been characterized, and of these forty-three utilize hypoxanthine in lieu of adenine for their purine requirements (8). The interconvertibility of the 5’-nucleotides of hypoxanthine and adenine, muscle inosinic and muscle adenylic acids, has been demonstrated through the rapid uptake of isotopic NH, into the 6-amino group of this adenylic acid (9). In addition, folic acid-deficient Escherichia coli produces (10, 11) 5(4)amino-4(5)-imidazolecarboxamide and it has been shown (12) that glycine (or threonine) in the medium stimulates the production of this imidazole. This, in conjunction with the data showing that glycine is a specific precursor of uric acid, supports the suggestion of the latter authors that this imidazole derivative plus formic acid is the immediate precursor of hypoxanthine and thence of other purines. If these arguments are valid and if hypoxanthine is converted to ade-