The overall regulation of purine metabolism

Purine nucleotides produced from any of the input processes, including the de novo synthesis and salvage of either the endogenous or exogenous purines, could be converted into nucleotides of other purines. IMP acts as the common intermediate in the inter-conversion between adenine and guanine nucleotides (see Figure below). This mechanism enables the cell to maintain a desired and constant composition of the nucleotide pool.

The following figure shows the inter-relationship between the different processes of purine metabolism

The effect of an increased exogenous preformed purine supply on purine metabolism

Ruminant animals receive an abundant supply of exogenous purines from the rumen microbes. These exogenous purines are absorbed mainly as the nucleosides and free bases, which can possibly enter the body pool of purines. The effects of this exogenous supply on the various pathways of purine metabolism can be viewed as follows:

1. The purine salvage is greatly enhanced and the de novo synthesis reduced

The increased supply of preformed purines will enrich the substrates for the purine salvage enzymes. Moreover, since the salvage of the preformed purines is energetically less expensive than the biosynthesis de novo, the consequence would therefore be an enhanced flow of purine salvage pathway. With an abundant exogenous supply of preformed purines, it could be speculated that this process would be exploited to its maximum extent to meet the tissues requirement for purines.

The effect on the de novo purine synthesis is manifested in two ways: firstly a depressed activity of PRPP aminotransferase (EC.3.4.4.14), the enzyme that catalyses the first reaction of the de novo synthesis. Since this enzyme could be inhibited by the feed-back of various purine nucleotides, with ATP and ADP being the most potent inhibitors, and secondly, a reduced supply of a substrate, PRPP (S-phosphoribosyl-1-pyrophosphate), the common substrate for both de novo and salvage pathways. The augmented flow of the purine salvage pathway diverts the PRPP away from the de novo synthesis process. Consequently with a large supply of preformed purines, the de novo synthesis could be reduced to a minimum extent or switched off. In both microorganisms and animal cells, a reduced rate of purine biosynthesis de novo following an exogenous supply of purines has been documented.

2. The excess load of preformed purines would be directed to degradation

The purine salvage process is also subjected to the feed-back control of the purine nucleotides. Once the requirement of the tissues is met (namely, a certain cellular level of purine nucleotides has been reached), a further loading of nucleotides will inhibit the activities of Ad-PRTase and Hx-PRTase. The regulation of activities of these enzymes affects not only the flow of the salvage pathway but also the uptake of the substrates into the cell. This is because the degree of uptake is proportional to the PRTase activity and appears to be obligatorily linked to the nucleotide formation. A sufficient formation of purine nucleotides thus tends to direct the nucleosides and free bases towards the degradation process for the formation of uric acid and allantoin.