Effect of azaserine on the biosynthesis of diphosphopyridine nucleotide in mouse.

The biosynthetic pathway of diphosphopyridine nucleotide has been formulated through a study of yeast autolysates, erythrocytes, and liver homogenates. Two such pathways have been described by these procedures. Each system ultimately utilizes the enzyme diphosphopyridine nucleotide pyrophosphorylase. In the first pathway, the enzyme produces diphosphopyridine nucleotide directly by coupling adenosine triphosphate to nicotinamide mononucleotide (I) ; in the second pathway, the enzyme couples adenosine triphosphate to nicotinic acid mononucleotide to form the nicotinic acid analogue of diphosphopyridine nucleotide (2). The nicotinic acid analogue of diphosphopyridine nucleotide is then amidated to produce diphosphopyridine nucleotide (3). The enzymes involved in both pathways appear to be fairly ubiquitous in biological systems (I, 4) and it is difficult to evaluate the importance of each system. Studies on diphosphopyridine nucleotide levels in erythrocytes after the administration of nicotinamide or nicotinic acid indicate that the main pathway of diphosphopyridine synthesis is through the formation of the nicotinic acid analogue of diphosphopyridine nucleotide, as only the latter compound can elevate the diphosphopyridine nucleotide level (5). Similar studies in mouse liver indicate the converse of the results obtained with erythrocytes; here nicotinamide was found to be much more active than nicotinic acid (6). Although the effects of nicotinamide in the mouse suggest that a pathway involving nicotinamide mononucleotide may be the main system in the liver, recent studies (7) have shown that the nicotinic acid analogue of diphosphopyridine nucleotide is also elevated after nicotinamide injections. Normal levels of diphosphopyridine nucleotide may be also altered by the administration of azaserine (8). The subcutaneous injection of this compound will reduce markedly the level of diphosphopyridine nucleotide in mouse liver in 2 hours. The mechanism by which this decrease occurs is not known; however, it appears likely that the turnover of diphosphopyridine nucleotide is affected. A study of the incorporation of the various moieties of di-