PRPP

AMP, ADP, and ATP = adenosine mono-, di-, and triphosphate IMP = inosine 5 -monophosphate AICAR = 5 -phosphoribosyl-5-amino-4-imida2olecarboxamide DAP = diaminopimelic acid PRPP = phosphoribosyl pyrophosphate a — KGA = a-ketoglutaric acid Orn = ornithine Cit = citnilline represents the one carbon unit lost to tetrahydrofolate as serine is converted to glycine. 

Figure20-2. The pentose phosphate pathway. ( ,— PRPP, 5-phosphoribosyl 1-pyrophosphate.)...

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

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)... 

Figure 34-7 summarizes the roles of the intermediates and enzymes of pyrimidine nucleotide biosynthesis. The catalyst for the initial reaction is cytosolic carbamoyl phosphate synthase II, a different enzyme from the mitochondrial carbamoyl phosphate synthase I of urea synthesis (Figure 29-9). Compartmentation thus provides two independent pools of carbamoyl phosphate. PRPP, an early participant in purine nucleotide synthesis (Figure 34-2), is a much later participant in pyrimidine biosynthesis.

Purine and pyrimidine biosynthesis parallel one another mole for mole, suggesting coordinated control of their biosynthesis. Several sites of cross-regulation characterize purine and pyrimidine nucleotide biosynthesis. The PRPP synthase reaction (reaction 1, Figure 34-2), which forms a precursor essential for both processes, is feedback-inhibited by both purine and pyrimidine nucleotides. 

Various genetic defects in PRPP synthetase (reaction 1, Figure 34-2) present clinically as gout. Each defect— eg, an elevated increased affinity for ribose 5-... 

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. 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

Hepatic purine nucleotide biosynthesis is stringently regulated by the pool size of PRPP and by feedback inhibition of PRPP-glutamyl amidotransferase by AMP and GMP. 

To deoxyribonucleotides through ribonucleotide reductase. Regulation Availability of PRPP. 

Activity of the enzyme catalyzing the formation of the 5-phos-phoribosyl-1-amine from PRPP is inhibited by purines. Synthesis of GMP requires ATP. 

The major difference between purine and pyrimidine de novo biosynthesis is that the pyrimidine ring is assembled and then added to PRPP (Fig. 20-1). With purines, the purine ring is built directly on the PRPP. 

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... 

Allopurinol and its major metabolite, oxypurinol, are xanthine oxidase inhibitors and impair the conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol also lowers the intracellular concentration of PRPP. Because of the long half-life of its metabolite, allopurinol can be given once daily orally. It is typically initiated at a dose of 100 mg/day and increased by 100 mg/day at 1-week intervals to achieve a serum uric acid level of 6 mg/dL or less. Serum levels can be checked about 1 week after starting therapy or modifying the dose. Although typical doses are 100 to 300 mg daily, occasionally doses of 600 to 800 mg/day are necessary. The dose should be reduced in patients with renal insufficiency (200 mg/day for CLcr 60 mL/min or less, and 100 mg/day for CLcr 30 mL/min or less). 

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