Salvage, of purines

There are basically two types of salvage. The first involves attachment of the base to PRPP with the formation of pyrophosphate. This pathway is available for salvage of purines and uracil but not for cytosine or thymine. The other pathway involves attachment of the base to ribose 1-phosphate, which occurs to some extent for most of the purines and pyrimidines. This second pathway requires the presence of specific... 

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

PRPP is an "activated pentose" that participates in the synthesis of purines and pyrimidines, and in the salvage of purine bases (see p. 294). Synthesis of PRPP from ATP and ribose 5-phosphate is catalyzed by PRPP synthetase (ribose phosphate pyrophosphokinase, Figure 22.6). This enzyme is activated by inorganic phosphate (Pi) and inhibited by purine nucleotides (end-product inhibition). [Note The sugar moiety of PRPP is ribose, and therefore ribonucleotides are the end products of de novo purine synthesis. When deoxy-ribonucleotides are required for DNA synthesis, the ribose sugar moiety is reduced (see p. 295).]... 

This enzyme represents a principal route for the return, or salvage, of purines such as hypoxanthine, adenine, and guanine to the monophosphate level. The activity requires a metal, preferably magnesium. 

Saivage enzymes Nucleoside phosphotransferases involved in the salvage of purines and pyrimidines in protozoans... 

An alternative mechanism of SAB action could involve its known effects on de novo purine biosynthesis (1, S) and/or nucleoside transport (5). The combined inhibitory effects of SAB and purine analogues on purine biosynthesis could result in sufficient depletion of intracellular nucleotide pools to result in enhanced cellular cytotoxicity. In addition, these effects would lead to an increased bioavailability of 5-phosphoribosyl-l-pyrophosphate (PRPP), the first enzymic product in the de novo pathway. Increased PRPP levels would enhance the activity of hypoxanthine phosphoribosyl transferase, leading to increased salvage of purine analogues. 

Purine nucleotides are required by the rapidly proliferating malaria parasite primarily for nucleic acid synthesis and energy metabolism. The malaria parasite cannot synthesize purines novo and depends for Its Intraerythrocytlc (IE) growth and development on salvage of purine bases from the host RBC and extracellular environment (2). We have shown with falciparum. In vitro, that hypoxanthlne is an essential purine base precursor for parasite Synthesis of adenosine and guanoslne nucleotides (3). Whetiier hypoxanthlne Is the malaria parasites preferred substrate vivo Is not known. 

PP-ribose-P is a sugar phosphate which is synthesized from ATP and ribose-5-phosphate in a reaction requiring magnesium and inorganic phosphate catalyzed by PP-ribose-P synthetase (Figure 1). The PP-ribose-P formed is a substrate in the first and probable rate-limiting reaction of purine synthesis de novo which is catalyzed by PP-ribose-P amidotransferase (PAT). In addition, PP-ri-bose-P is a substrate in the purine phosphoribosyltransferase reactions which constitute a pathway for the salvage of purine bases. 

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. 

Conversion of purines, their ribonucleosides, and their deoxyribonucleosides to mononucleotides involves so-called salvage reactions that require far less energy than de novo synthesis. The more important mechanism involves phosphoribosylation by PRPP (structure II, Figure 34-2) of a free purine (Pu) to form a purine 5 -mononucleotide (Pu-RP). 

Liver, the major site of purine nucleotide biosynthesis, provides purines and purine nucleosides for salvage and utilization by tissues incapable of their biosynthesis. For example, human brain has a low level of PRPP amidotransferase (reaction 2, Figure 34-2) and hence depends in part on exogenous purines. Erythrocytes and polymorphonuclear leukocytes cannot synthesize 5-phosphoribosylamine (strucmre III, Figure 34-2)... 

Lesch-Nyhan syndrome, an overproduction hyperuricemia characterized by frequent episodes of uric acid hthiasis and a bizarre syndrome of self-mutilation, reflects a defect in hypoxanthme-guanine phosphoribo-syl transferase, an enzyme of purine salvage (Figure 34—4). The accompanying rise in intracellular PRPP results in purine overproduction. Mutations that decrease or abohsh hypoxanthine-guanine phosphoribosyltrans-ferase activity include deletions, frameshift mutations, base substitutions, and aberrant mRNA splicing. 

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited disorder of purine metabolism and is inherited in an autosomal recessive manner (K18, V7). This enzyme deficiency results in an inability to salvage the purine base adenine, which is oxidized via the 8-hydroxy intermediate by xanthine oxidase to 2,8-di-hydroxyadenine (2,8-DHA). This produces crystalluria and the possible formation of kidney stones due to the excretion of excessive amounts of this insoluble purine. Type I, with virtually undetectable enzyme activity, found predominantly in Caucasians, is found in homozygotes or compound heterozygotes for null alleles. Type II, with significant APRT activity, found only in Japan, is related to a missense mu-... 

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. 

Purine ribonucleotide biosynthesis Pyrimidine ribonucleotide biosynthesis Salvage of nucleosides and nucleotides Sugar-nucleotide biosynthesis and conversions Other... 

Purine catabolism to uric acid and salvage of the poime bases hypoxanthine (derived from adenosine) and guanine are shown in 1-18-5. 

Answer D. IMP is a feedback inhibitor of PRPP amidophosphoribosyl transferase, the first reaction in the biosynthesis of purines. IMP is formed by the HPRT reaction in the salvage of hypoxanthine. 

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. 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

N-Ribohydrolases have been found to be involved in novel pathways of purine salvage in protozoan parasites as well as in nucleic acid repair, and exhibit other interesting biological activities [178]. In order to investigate the molecular electrostatic potential surface of the enzyme from the trypanosome Crithidia fasci-culata, several l,4-dideoxy-l,4-imino-D-ribitol derivatives were synthesized as nucleoside analogues and their inhibitory powers were tested [179,180]. In the course of this work, l,4-dideoxy-l,4-imino-l(S)-phenyl-D-ribitol (97) was found to inhibit this enzyme with K 30 nmol/1. 

Purine and pyrimidine nucleotides are essential for a vast number of biological processes such as the synthesis of RNA, DNA, phospholipids, glycogen, and the si-alylation and glycosylation of proteins. Both purines and pyrimidines can be synthesized de novo in mammalian cells through multistep processes. In addition to the de novo synthesis, purine nucleotides can also be synthesized via the salvage of... 

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 ... 

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