TRYPTOPHAN METABOLISM I. CONCERNING THE MECHANISM OF THE MAMMALIAN CONVERSION OF TRYPTOPHAN INTO KYNURENINE, KYNURENIC ACID, AND NICOTINIC ACID* BY CHARLES HEIDELBERGER,t MARY E. GULLBERG, AGNES FAY

One of the first metabolic products of tryptophan to be reported was kynurenic acid, which was isolated by Ellinger in 1904 (1) from the urine of dogs that had been fed the amino acid. He characterized the compound correctly except for the assignment of the carboxyl group to the 3 position in the quinoline ring, but its correct location at the 2 position was determined soon afterward (2). Another apparent metabolic product, kynurenine, was discovered in 1931 by Kotake and Iwao (3), who assigned an incorrect structure to this molecule. In 1943, however, Butenandt et al. (4) determined its structure and confirmed it by synthesis. A third metabolite, xanthurenic acid, was isolated from the urine of pyridoxine-deficient rats that had previously been fed tryptophan (5). Krehl et al. (6) in 1945 showed that rats would grow rapidly on low nicotinic acid diets containing corn, provided that additional tryptophan was added, and called attention to the possibility of a metabolic interrelation of this amino acid and nicotinic acid. They suggested that these results might be due at least in part to the intestinal flora. Shortly afterwards Rosen, Huff, and Perlzweig (7) demonstrated an increased excretion of nicotinic acid and N-methylnicotinamide in the urine of rats following the administration of tryptophan and suggested that tryptophan is converted into nicotinic acid. Since that time this conversion has been found to take place in humans (8) and several other mammals. A first understanding of the mechanism of this transformation resulted from the work of Beadle, Mitchell, and Nyc (9), who demonstrated that kynurenine is an intermediate in the conversion of tryptophan into nicotinic acid in mutant strains of Neuro-