The Enzymatic Conversion of Quinolinate to Nicotinic Acid Mononucleotide in Mammalian Liver.

It has been known for many years that tryptophan is converted to niacin by mammals (1) and Neurospora (2) and that 3-hydroxyanthranilate is an intermediate in this conversion (3). The steps between 3-hydrosyanthranilate and niacin have, homever, remained obscure until recently. A very active soluble oxidase present in mammalian kidney and liver converts 3-hydroxyanthranilate to the unstable acyclic compound 2-amino-3carboxymuconic semialdehyde, which spontaneously cyclizes to form quinolinate (4). Considerable evidence showing that quinolinate is converted to niacin in vivo has been accumulated. In .Veurospora crassa, one mutant accumulates qoinolinate in the medium when grown at eubopt,imal nicotinamide levels, and another mutant utilizes high levels of quinolinate in place of niacin (5). In rat)s, injection of quinolinate causes a a-fold increase in W-methylnicotinamicle excretion (6), and high levels of quinolinic acid can replace niacin in the diet, (5). Moreover, the injection of quinolinic arid-3H is followed by excretion of W-methylnicotinamide-3H in the urine (7). Recent)ly, the conversion of quinolinic acid-3H to niaciGH in chick embryos has also been demonat.ratcd (6). In spite of this evidence, the low efficiency of quinolinic acid for replacing niacGn in nutritional experiments and the failure to observe this conversion im vitro have led reviewers in this field t’o postulate an alternate pathway for niacin formation from 3-hydroxyanthranilate. Recently, Nishizuka and Hayaishi (9) have report.ed that quinolinate is converted to nicotinic acid mononucleotide in t,he presence of 5-phosphoribosyl-l-pyrophosphate by a soluble system obt.ained from rat liver. The same reaction has also been reported to occur in Bscherichia coli (10). This reaction apl)ears to be analogous t,o the formation of nicotinic acid mononucleotide from nicotinic acid as described by Imsande and Handler (11). Although the work of Nishizuka and Hayaishi clearly establishes a possible enzymatic basis for t,he conversion of tryptophan t,o niacin, it leaves unanswered several basic questions concerning this conversion. For example, are the kinetic parameters of thL5 system such that it. could reasonably be expected to account, for the conversion of tryptophan to niacin observed in vivo, is quinolinic acid rihotide formed as an intermediate, or does addit,ion of the ribosyl 5-phosphate moiety and decarboxylation of quinolinate occur in a concerted reaction,