Efficiency and regulation of pyrimidine synthesis

There are only a few studies dealing with the cellular uptake of orotic acid. The incorporation of orotic acid into whole cells can be stimulated more than 90-fold by a combination of PRPP and a heat labile factor [150], probably orotate phosphoribosyltransferase. It is assumed [151] that the enzyme attaches to the cell membrane and in the presence of external orotic acid and PRPP leads to the formation of internal orotidine 5 -phosphate. In bacteria the orotate is taken up similarly [151] by a process of group translocation across the membrane involving the participation of orotate phospjioribosyltransferase and requiring PRPP. 

Since the sequence of reactions in the orotate pathway was established mainly in studies with adult rat livers, there are continuing attempts to demonstrate a similar sequence of reactions in other biological systems. For example, the enzymes of the orotate pathway are not very active in fetal rat livers [187]. Orotic acid injected into pregnant females is incorporated to a lesser extent into fetal hepatic RNA than into hepatic RNA of adult rats although the placenta does not block the uptake of orotic acid. However, there is a considerable incorporation of orotic acid on the second day after birth [187] and the specific activity of the weanling rat hepatic RNA attains a superior value to that found in the adult rats. There are several reports dealing with the role of the orotate pathway during development [188-191]. 

For a long time it has not been known whether the brain itself supplies pyrimidine precursors for the synthesis of RNA de novo or whether these precursors must be supplied preformed from extraneural sources. Evidence has been obtained [192] that neural tissue has little capacity for synthesizing pyrimidine nucleotides for its own metabolic needs de novo. The incorporation studies in rats suggest that the brain utilizes preformed pyrimidines to a much greater extent than it utilizes the de novo pathway. This underlines the importance of the liver and other peripheral organs in the maintenance of normal RNA metabolism of the brain [192], although the brain contains the enzymes of pyrimidine synthesis de novo [193,194]. 

Measurements of the incorporation of labelled bicarbonate into orotic acid established the occurrence of the complete pathway of de novo 

On the other hand, the pattern of an increase of orotate phosphoribosyltransferase activity in regenerating rat livers suggests that the enzyme is not rate limiting for RNA synthesis at the early stages of liver regeneration [198,199], since the activities of enzymes of the orotate pathway either vary Uttle at the early post-operative stages or increase significantly only many 

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