Nucleotide salvage synthesis

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

Pyrimidine Nucleotide Metabolism, Nucleotide Salvage Synthesis... 

Salvage synthesis refers to the reuse of parts of nucleotides in resynthesizing new nucleotides. Salvage synthesis requires both breakdown and synthesis reactions in order to exchange the useful parts. 

See also Nucleotide Analogs in Medicine, Nucleotide Salvage Synthesis, Salvage Routes to Deoxyribonucleotide 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... 

While the PRTases salvage nucleobases within cells, nucleosides such as adenosine and uridine are present in the blood at much higher concentrations ( 1 pM) than the equivalent nucleobases, adenine and uracil. Indeed, the brain synthesizes pyrimidine nucleotides (UTP and CTP) via salvage synthesis from uridine produced by the liver and released into the circulation. Human cells may contain at least three types of nonspecific nucleoside transporters, and nucleosides are internalized more rapidly than nucleobases. 

UMP is a nucleotide intermediate in pyrimidine biosynthesis. It is produced by salvage synthesis and by the de novo pathway shown in Figure 22.10. 

Important enzymes in the salvage synthesis of nucleotides (Figure 22.2) are as follows ... 

Phospho-ot-D-ribosyl-l-pyrophosphate (PRPP) is an intermediate in both the de novo synthesis of nucleotides (Figure 22.1) and the salvage synthesis (reutilization) of nucleotides (Figure 22.2). 

Cytosolic thymidine kinase salvages exogenous thymidine extremely efficiently. Experiments with radiolabeled precursors show that dTTP derived from salvage synthesis is usually incorporated into DNA in preference to thymidine nucleotides generated by de novo synthesis. 

The main industrial method for the production of nucleotides is by enzymatic hydrolysis of yeast RNA to four nitrogenous bases with subsequent deamination of AMP to IMP, with CMP and UMP being waste products. Microbiological methods are being developed, based on the release of RNA derivatives, direct enzymatic production of nucleotides that are not RNA derivatives, and salvage synthesis (conversion of bases or nucleosides... 

Non- oxidative branch Pentose-5 -Phosphates Ribose-5-P 2 deoxy ribose-5-P 5 -phosphoribosyl-1 -pyrophosphate (PRPP) i) Structural components of nucleotides a. Basal structural component of RNA b. Basal structural component of DNA c. Precursor of both de novo and salvage synthesis of nucleotides ii) Intermediate products of purine metabolism and act as precursor molecules of cofactors, e g., riboflavin, flavin mononucleotide (FMN), flavin adenine di nucleotide (FAD) iii) Precursor of the amino acid. Histidine. 

Inosine monophosphate dehydrogenase (EVDPDH) is a key enzyme of purine nucleotide biosynthesis. Purine synthesis in lymphocytes exclusively depends on the de novo synthesis, whereas other cells can generate purines via the so-called salvage pathway. Therefore, IMPDH inhibitors preferentially suppress DNA synthesis in activated lymphocytes. 

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In patients with Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation, Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. These patients also all have hyperuricemia because purines cannot be salvaged. 

Figure 1-18-1. Nucleotide Synthesis by Salvage and De Novo Pathways...

The de novo synthesis of inosinic acid The salvage pathways Purine nucleotide interconversions Other enzymes... 

De novo synthesis of purines and pyrimidines yields the monophosphates IMP and UMP, respectively (see p. 188). All other nucleotides and deoxynucleotides are synthesized from these two precursors. An overview of the pathways involved is presented here further details are given on p. 417. Nucleotide synthesis by recycling of bases (the salvage pathway) is discussed on p. 186. 

A. Salvage pathways allow synthesis of nucleotides from free purines or pyrimidines that arise from nucleic acid degradation or dietary sources, which is more economical for the cell than de novo synthesis. 

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