It has generally been taken for granted that the inborn error of metabolism underlying primary gout is to be sought in one of the enzyme:: concerned specifically with de novo purine biosynthesis, or else in some abnormality of renal tubular transfer of uric acid, but recent developments suggest that the search should be broadened to include an anomaly in the metabolism of amino acids. The first hint of this came when the initial experiments with glycine-Nl5 administration to gouty subjects disclosed greater than normal isotope incorporation into uric acid in some cases, indicating that "in the gouty subject an unusually large uricotelic component may o ~c u r , " ~~~ and that "a disproportionate quantity of simple nitrogen and carbon precursors of uric acid is diverted from the main metabolic channels culminating in urea and carbon dioxide formation to pathways leading to urate formation."3 More recently it has been suggested that in primary gout there may be a defect in the utilization specifically of the amino acid, glutamine, for the formation of ammonia by the kidney, the excess glutamine being recycled and utilized instead for synthesis of extra urea and uric acid, and excretion as s ~c h . ~, ~
In this view, overproduction of uric acid in primary gout would be the result of an intrinsic error, not in d e novo purine biosynthesis per se but in amino acid (glutamine) metabolism, with increased formation of uric acid as one of the secondary consequences.
Whatever the inborn metabolic defect( s ) of primary gout may prove ultimately to be, it seems appropriate at this juncture to define more clearly the relationships between uric acid metabolism and amino acid metabolism, not only in man, a rather special case, but, for better perspective, over the wide range of evolutionary development. The first point to be made in this connection is that consistently throughout the phylogenetic scale, including man, uric acid is elaborated ultimately from amino acids almost exclusively. At all levels of biological organization (plants, bacteria, yeasts, birds, mammals, etc. ) de novo biosynthesis of inosinic acid, the initial purine formed de novo, involves uniformly (with few minor deviations) derivation of N-9 and N-3 from the amide nitrogen of glutamine; N-7, C-5 and C-4 from glycine; N-1 from aspartic acid; C-2 and C-8 from the P-carbon cf serine, by way of tetrahydrofolic acid derivatives; and C-6 from bicarbonate, of which some proportion originates ultimately from amino acid carbon.6 Thus of the nine atoms that make up the framework of the uric acid molecule, six are contributed by amino acids di-*Based on studies supported in part by a grant-in-aid, A-162, from the National In-