Quinolinic Acid Metabolism

Since the observation (1) that tryptophan and nicotinic acid are mutually interchangeable, within limits, in supporting the growth of rats, considerable evidence has accumulated which indicates that biosynthesis of nicotinic acid can proceed from tryptophan (2-5). Unequivocal evidence for this transformation was provided by the experiments of Heidelberger et al. (6) who fed labeled tryptophan @I-indolyl-3-C14-a-aminopropionic acid) and found that the Nr-methylnicotinamide isolated from the urine contained Cl4 in the carboxamide group. Studies with Neurospora have demonstrated a similar synthesis (7, 8) involving kynurenine and 3-hydroxyanthranilic acid as intermediates. That the synthesis proceeds by this pathway in the rat is suggested by the demonstration (9) that 3-hydroxyanthranilic acid replaces tryptophan or nicotinic acid for growth in the rat and increases the excretion of nicotinic acid in the urine (10). Recently work from this laboratory (11, 12) has shown that quinolinic acid is excreted by the rat following tryptophan or 3-hydroxyanthranilic acid administration. While this suggests that quinolinic acid is another intermediate, formed by oxidative cleavage of the beneenoid nucleus of 3-hydroxyanthranilic acid, quinolinic acid has been reported inactive for the growth of Neurospora crassa mutants (7, 9). The studies reported here concern the ability of quinolinic acid to replace nicotinic acid in the diet of the rat and the effects of the incorporation of the probable intermediates into the diet on the urinary excretion of nicotinic acid, N1-methyhricotinamide, and quinolinic acid. The failure of quinolinic acid at low levels to support the growth of N. crassa has been confirmed. At higher levels, however, mutant 4540 responded, while mutant 3416 did not. Quinolinic acid has been isolated from the medium of mutant 3416 following growth with limiting amounts of nicotinamide.