Studies on the Metabolism of the Benzene Ring of Tryptophan in Mammalian Tissues. I. Enzymic Formation of Glutaric Acid from 3-hydroxyanthranilic Acid.

Hankes and Henderson (I), Gholson et al. (2), and Gholson and Henderson (3) demonstrated that nL-tryptophan-7cu-14C was metabolized by the rat to r4C02 via acetate-1-r4C. Subsequently, Gholson et al. (4) indicated that 3-hydroxyanthranilic acid was an intermediate in the major pathway for the degradation of the benzene ring of tryptophan. Further experiments in viva have provided evidence that glutaric acid may be an intermediate in this conversion (5). However, all previous experiments in vitro indicated that quinolinic acid (6) and picolinic acid (7) are the only stable products formed from 3-hydroxyanthranilic acid in mammalian liver. These pyridinecarboxylic acids, however, are not degraded to CO2 even in viva, although recent reports from our laboratory have shown that quinolinic acid was converted to niacin ribonucleotide in the presence of 5-phosphoribosyl 1-pyrophosphate (8, 9). Picolinic acid is excreted in the urine as a glycine conjugate when administered to mammals (10). Preliminary reports from our laboratory have described briefly an enzyme system in cat liver extracts, which catalyzes the formation of glutaric acid from 3-hydroxyanthranilic acid (11, 12). The enzymes involved in this pathway have now been purified and characterized, and the intermediates have been identified. Available evidence indicates the sequence of reactions in Scheme 1 as a complete degradative pathway of tryptophan in mammalian liver. The new pathway will be referred to hereafter as the glutarate pathway of tryptophan metabolism. The present communication is concerned with the enzymic formation of oc-ketoadipic acid and glutaryl coenzyme A from 3-hydroxyanthranilic acid. Details of the purification and characterization of the enzymes as well as identification of the intermediates of the glutarate pathway will be described in the following papers of this series.