Studies on the Biological Activity of Nicotinylalanine, an Analogue of ICynurenine*

Considerable evidence has been obtained that 3-hydroxyanthranilic acid and quinolinic acid can be converted to niacin in the intact rat (2-9). The usually low yield of niacin from these compounds suggested that another pathway from tryptophan to niacin might exist. Thus, kynurenine or hydroxykynurenine might be converted to niacin through an intermediate such as y-(3-pyridyl)-y-oxo-ar-aminobutyrate (referred to as nicotinylalanine) via ring oxidation and rearrangement similar to that known to occur with 3-hydroxyanthranilic acid (Fig. 1). To test this hypothesis, nicotinylalanine was synthesized and tested as a possible precursor of niacin in the intact rat and in tissue preparations. Nicotinylalanine is relatively nontoxic, and its intraperitoneal injection was followed by an increase in urinary excretion of N-methylnicotinamide. When nicotinylalanine was incubated with rat liver homogenates, it appeared to be converted to nicotinic acid by a kynureninase-like enzyme. In studies with tryptophan-3-C14, data were obtained indicating that nicotinylalanine is not an intermediate in the conversion of tryptophan to niacin. However, it was found that nicotinylalanine is an effective inhibitor of kynureninase and kynurenine hydroxylase in vivo and in vitro.