INTRAMOLECULAR DISTRIBUTION OF URIC ACID-N15 AFTER ADMINISTRATION OF GLYCINE-N15 AND AMMONIUM-N15 CHLORIDE TO GOUTY AND NONGOUTY SUBJECTS*

Abstract

Four nongouty and 6 subjects with primary gout were given glycine-N15, and 2 nongouty and 6 subjects with primary gout were given the equivalent amount of N15 as ammonium-N15 chloride. The abundance and intramolecular distribution of uric acid-N15 were then determined and compared in the gouty and nongouty. Gouty overexcretors of uric acid consistently incorporated grossly excessive N15 into uric acid, as compared with the nongouty, whether given glycine-N15 or ammonium-N15. The gouty normal excretors did not have unequivocally greater than normal uric acid-N15 abundance after glycine-N15 administration unless a correction was made for their expanded uric acid pools. After ammonium-N15 administration, the uric acid-N15 abundance was some-what greater than normal in 2 gouty normal excretors even without such correction. After administration of glycine-N15, N-7 was enriched more than any other one uric acid nitrogen in both gouty and nongouty subjects. However more of the total uric acid-N15 appeared initially at N-(l + 3 + 9) in the gouty (normal as well as overexcretors) than in the nongouty. Thus the gouty subjects uniformly utilized more glycine nitrogen for uric acid biosynthesis, not only directly as intact glycine and after recycling of reconstituted glycine (N-7), but also after transfer of glycine nitrogen to the amide nitrogen of glutamine (N-9,3) and the amino nitrogen of aspartic acid (N-1). After administration of ammonium-N15, most of the uric acid-N15 appeared initially at N-(9 + 3) in both gouty and nongouty subjects[long dash]in gross excess in the gouty overexcretors, however, and in somewhat greater than normal abundance (even before correction for expanded uric acid pools) in the one gouty normal excretor so studied. With subsequent randomization of N15, presumably by transamination, the distribution of isotope among the four uric acid nitrogens became more uniform. There appear to be differences between gouty and normal man in respect to the utilization of precursor amino acids, nitrogen being diverted in the gouty from competing pathways to the sequential reactions of de novo uric acid biosynthesis. Given the same load of amino acid precursors, whether free or combined as dietary protein, the gouty subject apparently makes available to the enzymes initiating de novo uric acid biosynthesis more substrate than does normal man; this results in pronounced overproduction of uric acid in some instances, less pronounced or inferential overproduction in others. It is suggested that the underlying inborn metabolic error in primary gout, at least in some cases, may be an innate deficiency of one or more enzymes concerned with the disposition of amino acid nitrogen by metabolic pathways in competition with de novo uric acid biosynthesis.