Nucleic acid bases salvage pathways

Two types of pathways lead to nucleotides the de novo pathways and the salvage pathways. De novo synthesis of nucleotides begins with their metabolic precursors amino acids, ribose 5-phosphate, C02, and NH3. Salvage pathways recycle the free bases and nucleosides released from nucleic acid breakdown. Both types of... 

Just as orotic acid is converted to a ribonucleotide in step e of Fig. 25-14, other free pyrimidine and purine bases can react with PRPP to give monoribonucleotides plus PP . The reversible reactions, which are catalyzed by phosphoribosyltransferases (ribonucleotide pyrophosphorylases), are important components of the salvage pathways by which purine and pyrimidine bases freed by the degradation of nucleic acids are recycled.273 However, thymine is usually not reused. Thymine will react with deoxribose 1-P to form thymidine plus inorganic phosphate (thymidine phosphorylase), and thymidine is rapidly... 

In addition to the pathways for synthesis de novo, mammalian cells and microorganisms can readily form mononucleotides from purine bases and their nucleosides and to a lesser extent from pyrimidine bases and their nucleosides. In this way bases and nucleosides formed by constant breakdown of mRNA and other nucleic acids can be reconverted (or salvaged ) to useful nucleotides, and the energy expended by the cell in synthesizing the bases is retained. 

Salvage pathway. A family of reactions that permits nucleosides or purine and pyrimidine bases resulting from the partial breakdown of nucleic acids, to be reutilized in nucleic acid synthesis. 

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. 

The free nucleotides, nucleosides, and bases which are present in physiological fluids result from the catabolism of nucleic acids, enzyme-catalyzed degradation of bodily tissues, anabolic pathways such as the de novo or salvage pathways, or dietary intake. 

In addition to major nucleosides and bases, modified nucleosides and bases have also been isolated from tRNA hydrolysates and in physiological fluids of man. Unlike the major nucleic acid components, the methylated or otherwise structurally altered purine and pyrimidine compounds are not recycled in the salvage pathways but are excreted. It has been suggested that the measurement of these modified compounds may provide an indicator of the rate of tRNA metabolism. Furthermore, the altered patterns of excretion for these compounds may be used as biomarkers for the detection of disease states and aberrations in metabolic pathways. 

In the purine salvage pathway, purine bases obtained from the normal turnover of cellular nucleic acids or (to a lesser extent) from the diet are reconverted into nucleotides. Because the de novo synthesis of nucleotides is metabolically expensive (i.e., relatively large amounts of phosphoryl bond energy are used), many cells have mechanisms to retrieve purine bases. Hypoxanthine-guaninephos-phoribosyltransferase (HGPRT) catalyzes nucleotide synthesis using PRPP and either hypoxanthine or guanine. The hydrolysis of pyrophosphate makes these reactions irreversible. 

The salvage pathways utilized by these pathogens are similar to those used in mammalian cells (Fig. 6.1). In many cases the pathways differ in certain aspects, perhaps in response to the purine composition of the parasite s host environment. These routes permit cells to utilize exogenous purines derived from the degradation of nucleic acids or nucleotides. In mammalian cells and many parasitic organisms, purine bases... 

N. and deoxynucleosides can be synthesized via a Salvage pathway (see). TTiey are also produced by hydrolysis of nucleic acids and nucleotides. Nucleoside phosphorylases and deoxynucleoside phosphorylases catalyse the reversible, phosphate-dependent cleavage of N. and deoxyribonucleosides, forming ribose 1-phosphate or deoxyribose 1-phosphate and the free base. N. and deoxyribonucleosides can be converted into their corresponding nucleotides by the action of specific kinases. 

The purine salvage pathway enzyme HGPRT phosphoribosylates hypoxanthine and guanine, which allows the free bases to be reused as precursors for nucleic acid synthesis. The purine analogues, 8-azaguanine (8AG) and 6-thioguanine (6TG), are also substrates for HGPRT. After further phosphorylation, 8AG and 6TG ribonucleotides become substrates for nucleic... 

Since there has been no evidence presented to support the hypothesis that free adenine can be formed de novo in biological systems from small molecule precursors, and furthermore, since purines have never been reported to have been essential dietary additions, the formation of nucleotides from free purines may be looked upon as a minor biosynthetic pathway. Undoubtedly, there is some utilization of free purines which are derived from the intestinal tract as well as from catabolic events within the cell. The term salvage pathway has been aptly applied to the reactions utilizing free bases for nucleic acid synthesis (206). 

Since synthesis of pyrimidine and purine nucleotides de novo (anew) is energetically demanding, it may occur using heterocyclic bases from dietary sources or from those released by the turnover of nucleic acids. Such reactions, called salvage pathways (Figure 16.7) since they enable the reutilization of existing bases, facilitate considerable savings in ATP. 

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