Salvage pathway

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. 

Free purines may be joined with PRPP to produce mononucleotides by one of two enzymes. 

The reaction shown below is catalyzed by adenine phosphoribosyltransferase (APRT). 

The following reactions are catalyzed by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). 

Salvage of purine nucleosides is achieved by phosphorylation with ATP as the phosphate donor. 

All the required enzymes occur in the cytosol. This is also true for enzymes of salvage pathways, nucleotide interconversion, and degradation. 

De novo synthesis is particularly active in the liver and placenta. Nonhepatic tissues (e.g., bone marrow) depend on preformed purines that are synthesized in the liver and transported by red blood cells. They are very effective in salvaging the purines and exhibit little or no activity of xanthine oxidase, which oxidizes free purines. 

Reutilization of purine bases after conversion to their respective nucleotides constitutes salvage pathways. These pathways are particularly important in extrahepatic tissues. Purines arise from several sources intermediary metabolism of nucleotides, degradation of polynucleotides, and dietary intake. Quantitatively, the first two sources are the more important. Salvage occurs mainly by the phosphoribosyltransferase reaction  

A quantitatively less significant salvage pathway uses purine nucleoside phosphorylase and nucleoside kinase  

The phosphorylase can catalyze the formation of inosine or deoxyinosine, and of guanosine or deoxyguano-sine, but not adenosine or deoxyadenosine. However, the last two nucleosides can be converted to inosine and deoxyinosine by adenosine deaminase. The normal function of the phosphorylase appears to be the formation 

One enzyme uses either guanine or hypoxanthine (adenine with the amino group replaced by an OH). A second enzyme uses free adenine. A third enzyme is specific for uracil and thymine. All the enzymes carry out the same reaction transfer of the free base to the ribose-5 -monophosphate of PRPP, forming a nucleoside-5 monophosphate (NMP). 

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Pentostatin (deoxycoformycin Fig. 4) is a purine isolated from cultures of Streptomyces antibioticus. Its mode of action involves inhibition of adenosine deaminase, which plays a key role in purine salvage pathways and DNA synthesis. As a consequence, deoxyadenosine triphosphate (dATP) is accumulated, which is highly toxic to lymphocytes. This is associated with augmented susceptibility to apoptosis, particularly in T cells. 

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. 

Guanine Phosphoribosyl Transferase. Guanine phosphoribosyl transferase (GPRT) is one of the enzymes of the purine salvage pathway, which is needed by protozoa because they lack the ability to synthesize purine nucleotides. 

FIGURE 3.27 Dioxygenation of enediol to formate + CO in the methionine salvage pathway. 

Wray JW, RH Abeles (1995) The methionine salvage pathway in Klebsiella pneumoniae and rat liver. J Biol Chem 270 3147-3153. 

The free bases of the purines can be salvaged to spare de novo synthesis. The only hard thing is remembering what the names stand for. HGPRTase is hypoxanthine-guanine phosphoribosyltransferase, and it makes both IMP and GMP. A separate enzyme exists for the salvage of adenine. The salvage pathways are included in Fig. 19-1. 

Salvage Pathways Recovering Mono-ubiquitin Adducts and Recycling Polyubiquitin... 

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. 

The nucleosides are converted back to nucleosides is reactions known as salvage pathways (Chapter 20). RNA supplements in the diet are also hydrolysed to form nucleosides, which can be taken up by cells in the body to form nucleotides. Although proliferating cells can synthesise nucleotides de novo, provision of nucleosides bypasses a considerable amount of biochemistry. This is important, for example, in lymph nodes for proliferating immune cells in the bone marrow and also for stem cells in the crypts of the villi (Chapter 20). 

A summary of some of these processes is as follows synthesis of phospholipids and cholesterol de novo synthesis of ribonucleotides synthesis of RNA de novo synthesis of deoxyribonucleotides regulation of synthesis of deoxyribonucleotides salvage pathways duplication of DNA transcription and translation (polypeptide synthesis). After this series of topics, those of fuels and ATP generation, mitosis and, finally, regulation of the cycle, are described and discussed. 

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. 

Anderson, R.M., Bitterman, K.J., Wood, J.G., Medvedik, O., Cohen, H., Lin, S.S., Manchester, J.K., Gordon, J.l. and Sinclair, D.A. (2002) Manipulation of a nuclear NAD salvage pathway delays aging without altering steady-state NAD levels./ournoi of Biological Chemistry, 277, 18881-18890. 

Kinsella AR, Smith D. Pickard M (1997) Resistance to chemotherapeutic antimetabolites a function of salvage pathway involvement and cellular response to DNA damage. Br J Cancer 75 935-945... 

When nucleoside analogs, such as cytosine arabinoside (AraC), azidothymidine (zidovudine orAZT), and dideoxyinosine (ddi), are converted into the corresponding nucleotides by salvage pathways, they can be Incorporated into nascent DNA strands by DNA polymerases. 

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