De novo pyrimidine nucleotide metabolism

See also De Novo Biosynthesis of Purine Nucleotides, De Novo Pyrimidine Nucleotide Metabolism, Nucleotide Salvage Synthesis... 

See also The Importance of PRPP, De Novo Biosynthesis of Purine Nucleotides, Excessive Uric Acid in Purine Degradation, De Novo Pyrimidine Nucleotide Metabolism, Nucleotide Salvage Synthesis, Deoxyribonucleotide Biosynthesis, Biosynthesis of Thymine Deoxyribonucleotides, Salvage Routes to Deoxyribonucleotide Synthesis... 

CMP is a pyrimidine nucleotide that is an intermediate in several metabolic pathways. It arises from synthesis of phosphatidic acid-containing compounds. In addition to being an intermediate in de novo pyrimidine biosynthesis, it participates in the reactions that follow ... 

Free purine and pyrimidine bases are constantly released in cells during the metabolic degradation of nucleotides. Free purines are in large part salvaged and reused to make nucleotides, in a pathway much simpler than the de novo synthesis of purine nucleotides described earlier. One of the primary salvage pathways consists of a single reaction catalyzed by adenosine phosphoribosyltransferase, in which free adenine reacts with PRPP to yield the corresponding adenine nucleotide ... 

Purine and pyrimidine nucleotides are essential components of many biochemical molecules, from DNA and RNA to ATP and NAD. In recent years, the pyrimidine and especially the purine metabolism of parasitic helminths have been investigated extensively, mainly because they are different from the pathways in the mammalian host such that they have potential as targets for chemotherapeutic attack. For a review of purine and pyrimidine pathways in parasitic helminths and protozoa, see Berens et al. (1995). Although parasitic helminths do not synthesize purines de novo, but obtain them from the host, they do possess elaborate purine salvage pathways for a more economical management of this resource. Pyrimidines, on the other hand, are synthesized de novo by all parasitic flat-worms studied so far and, as with mammalian... 

The so-called salvage pathways are available in many cells to scavenge free purine and pyrimidine bases, nucleosides, and mononucleotides and to convert these to metabolically useful di- and trinucleotides. The function of these pathways is to avoid the costly (energy) and lengthy de novo purine and pyrimidine biosynthetic processes. In some cells, in fact, the salvage pathways yield a greater quantity of nucleotides than the de novo pathways. The substrates for salvage reactions may come from dietary sources or from normal nucleic acid turnover processes. 

Nucleotides are synthesized by two types of metabolic pathways de novo synthesis and salvage pathways. The former refers to synthesis of purines and pyrimidines from precursor molecules the latter refers to the conversion of preformed purines and pyrimidines—derived from dietary sources, the surrounding medium, or nucleotide catabolism—to nucleotides, usually by addition of ribose-5-phosphate to the base. De novo synthesis of purines is based on the metabolism of one-carbon compounds. 

Nucleotides are the building blocks of the nucleic acids. They also regulate metabolism and transfer energy. The purine and pyrimidine nucleotides are synthesized in both de novo and salvage pathways. 

Purines and pyrimidines are required for synthesizing nucleotides and nucleic acids These molecules can be synthesized either from scratch, de novo, or salvaged from existing bases. Dietary uptake of purine and pyrimidine bases is low, because most of the ingested nucleic acids are metabolized by the intestinal epithelial cells. 

Dietary uptake of purine and pyrimidine bases is minimal. The diet contains nucleic acids and the exocrine pancreas secretes deoxyribonuclease and ribonucle-ase, along with the proteolytic and lipolytic enzymes. This enables digested nucleic acids to be converted to nucleotides. The intestinal epithelial cells contain alkaline phosphatase activity, which will convert nucleotides to nucleosides. Other enzymes within the epithelial cells tend to metabolize the nucleosides to uric acid, or to salvage them for their own needs. Approximately 5% of ingested nucleotides will make it into the circulation, either as the free base or as a nucleoside. Because of the minimal dietary uptake of these important molecules, de novo synthesis of purines and pyrimidines is required. 

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]. 

Biosynthesis de novo is the initial regulatory level to be considered. The first complete nucleotide to be formed in the purine biosynthetic pathway is inosine-5 -phosphate (IMP), and that in the pyrimidine pathway is uridine-5 -phosphate (UMP). The two pathways are operationally separate and distinct and metabolically related only in that they share some common participants such as glutamine, CO2,... 

What, then, is the significance of the allopurinol and oxipurinol ribonucleotides Their relationship to pyrimidine metabolism will be discussed by Dr. Hitchings [13]. Feedback inhibition of de novo purine synthesis has been found to occur in man [13] and animals [3,15] treated with allopurinol and oxipurinol. From the quantitative data presented here, it seems unlikely that allopurinol ribonucleotide can be responsible for this effect. In Table 4 are shown the pool sizes of some of the naturally occurring nucleotides, as well as the expected levels of allopurinol ribonucleotide. 

The purine and pyrimidine bases are the building blocks of DNA and RNA, in which they are incorporated as nucleotides. All purines and pyrimidines are produced by de novo synthesis there is a continuous turnover. The majority of the purine and pyrimidine bases (and their nucleosides) has a strong UV-absorbance, facilitating their detection by HPLC. Humans produce uric acid as the end product of purine catabolism, its concentration may serve as an indicator of purine metabolism. 

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