Pathway of pyrimidine synthesis de novo

Higher organisms and many micro-organisms do hot require exogenous pyrimidines and can synthesize pyrimidine nucleotides from simple precursors. In 1944 it became apparent that orotic acid is involved in the synthesis of pyrimidines de novo and a few years later it was evident that it is a precursor of nucleic acids [70,71]. 

The small-molecule precursors of orotic acid were identified by Reichard and Lagerkvist [72]. During in vitro incubation, liver slices incorporated labelled ammonia, bicarbonate and aspartate into pyrimidine components of RNA. When the slices were incubated with the labelled precursors in the presence of extracellular orotate, isotopes were found in this extracellular fraction. In this way, orotic acid was recognized as an intermediate in pyrimidine synthesis de novo. The labelled orotate was chemically degraded and small molecules identified as the precursors of particular atoms of the orotate ring, as shown in the following scheme  

Nutrition studies in bacteria indicated that carbamoyl aspartate (also known as ureidosuccinate) is an intermediate in pyrimidine biosynthesis. Finally, uridine nucleotides were found as end products of pyrimidine synthesis de novo [73]. The sequence of reactions leading to the synthesis of UMP is designated as the orotate pathway or pyrimidine synthesis de novo in distinction to the salvage pathway. 

The salvage pathway utilizes preformed pyrimidines and purines for the synthesis of nucleic acids and is highly active in various types of cells. Uridine kinase plays a key role in the pyrimidine salvage pathway and its concentration is considered to reflect the relative efficiency of the system in utilizing preformed pyrimidines [74]. Adenosine kinase plays a similar role in making use of preformed purines [75]. It should be noted, however, that uridine and adenosine kinases are not the only enzymes involved in the salvage pathway and other deoxynucleoside kinases, phosphorylases, and phosphoribosyltransferases [76] also have important roles. 

As already mentioned, carbamoyl aspartate was recognized as an intermediate in the synthesis of orotic acid [77]. In ureoteUc livers, it is 

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