Regulatory Mechanisms In Purine Biosynthesis

Abstract

The distinction is made between immediate precursors of the purine ring (glycine, glutamine, aspartate, formyl tetrahydrofolate, bicarbonate) and ultimate precursors from which the immediate precursors are formed in the liver (amino acids, ammonia, glucose derivatives). In isolated hepatocytes from well-fed chickens addition of amino acids or ammonium chloride plus lactate caused relatively small increases in the rate of urate synthesis, but in hepatocytes from 72-hr fasted chickens the rate was much increased when alanine or asparagine were added as the only substrates. Other amino acids, when added alone, had no major effects on the rate of urate synthesis. The exceptional effect of alanine and asparagine is due to the ready formation of the immediate precursors from these substances. When chickens were given a high protein diet egg white (or blow-fly maggots) the capacity of the hepatocytes for urate synthesis may increase 6-fold over the controls fed a standard diet. Conditions are described under which glutamine, serine, glycine plus formate, ribose or glucose can increase the rate of urate synthesis. This implies that the availability of these precursors can be rate-limiting. Ammonium chloride at relatively low concentrations inhibited the rate of urate synthesis in the presence of lactate or alanine. At the same time the synthesis of glucose from lactate or alanine was inhibited. These inhibitions were parallelled by the increase in the rate of glutamine synthesis. Thus in the presence of ammonium chloride the metabolism of gluconeogenic precursors was diverted from the pathway of gluconeogenesis to the synthesis of glutamine. In the presence of excess of ammonia the synthesis of glutamine is the primary mechanism of detoxication of ammonia in the avian liver. Urate synthesis, like urea synthesis, may be looked upon as a cyclic process with either phosphoribosylpyrophosphate or ribose acting as the “carrier” on which the purine ring is assembled. The energy requirement of urate synthesis depends on whether phosphoribosylpyrophosphate is regenerated from IMP by pyrophosphorylase or by phosphorylation and pyrophosphorylation of ribose. It is 6 or 9 pyrophosphate bonds of ATP, respectively. Other factors regulating the rate of purine and urate synthesis are discussed.