5-Phosphoribosyl-1 -pyrophosphate synthetase

Phosphoribosyl pyrophosphate synthetase (from human erythrocytes, or pigeon or chicken liver) [9015-83-2] Mr 60,000, [EC 2.7.6.1]. Purified 5100-fold by elution from DEAE-cellulose, fractionation with ammonium sulfate, filtration on Sepharose 4B and ultrafiltration. [Fox and Kelley J Biol Chem 246 5739 197h, Flaks Methods Enzymol6 158 1963 Kornberg et al. J Biol Chem 15 389 7955.]... 

The first step of this sequence, which is not unique to de novo purine nucleotide biosynthesis, is the synthesis of 5-phosphoribosylpyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate. Phosphoribosyl-pyrophosphate synthetase, the enzyme that catalyses this reaction [278], is under feedback control by adenosine triphosphate [279]. Cordycepin interferes with thede novo pathway [229, 280, 281), and cordycepin triphosphate inhibits the synthesis of PRPP in extracts from Ehrlich ascites tumour cells [282]. Formycin [283], probably as the triphosphate, 9-0-D-xylofuranosyladenine [157] triphosphate, and decoyinine (LXXlll) [284-286] (p. 89) also inhibit the synthesis of PRPP in tumour cells, and this is held to be the blockade most important to their cytotoxic action. It has been suggested but not established that tubercidin (triphosphate) may also be an inhibitor of this reaction [193]. 

This enzyme [EC 2.7.6.1], also known as phosphoribosyl pyrophosphate synthetase, catalyzes the reaction of ATP with D-ribose 5-phosphate to produce AMP and 5-phospho-a-D-ribose 1-diphosphate. dATP can also function as a substrate. 

Phosphoribosyl pyrophosphate synthetase (from human erythrocytes, or pigeon or... 

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

HGPRT hypoxanthine guanine phosphoribosyl transferase NSAID nonsteroidal anti-inflammatory drug PRPP phosphoribosyl pyrophosphate (synthetase)... 

The syntheses and uses of these and other analogous complexes is reviewed elsewhere (15-17). The complex A Co(III)(NH3)4ATP is a substrate for hexoki-nase, whereas the A isomer is not, which suggests that the bidentate complex A MgATP is the natural substrate (19). The complex A Co(III)(NH3)4ATP is a substrate for phosphoribosyl pyrophosphate synthetase (20). The results of many similar studies are compiled in the review by Eckstein (21). 

In some cases of gout a twofold increased activity of the phosphoribosyl pyrophosphate synthetase has been demonstrated in fibroblasts with increased production of PRPP. The possibility of an inhibitor causing the increased activity was excluded. This is another example of an enzyme increase in hereditary disease [217]. 

Washed and hemolyzed erythrocytes of the patients were used for the determination of phosphoribosyl-pyrophosphate synthetase (PRPP-synthetase) according to Hershko (8), and for purinephosphoribosyltransferases according to Kelley. Uric acid was determined enzymatically using Boehringer kit ... 

Table 3 Adenine phosphoribosyltransferase, hypoxanthine guanine phosphoribosyltransferase, and phosphoribosyl-pyrophosphate synthetase activities in hemolysates from patients with benign symmetric lipomatosis ...

Switzer, R. L. 1967. End product inhibition of phosphoribosyl-pyrophosphate synthetase. (Abstract). Fed. Proc. 26 560. 

Seasonal variations in the metabolic fate of adenine nucleotides prelabelled with [8—1-4C] adenine were examined in leaf disks prepared at 1-month intervals, over the course of 1 year, from the shoots of tea plants (Camellia sinensis L. cv. Yabukita) which were growing under natural field conditions by Fujimori et al.33 Incorporation of radioactivity into nucleic acids and catabolites of purine nucleotides was found throughout the experimental period, but incorporation into theobromine and caffeine was found only in the young leaves harvested from April to June. Methy-lation of xanthosine, 7-methylxanthine, and theobromine was catalyzed by gel-filtered leaf extracts from young shoots (April to June), but the reactions could not be detected in extracts from leaves in which no synthesis of caffeine was observed in vivo. By contrast, the activity of 5-phosphoribosyl-1-pyrophosphate synthetase was still found in leaves harvested in July and August. 

Figure 10.7 Schematic representation of the formation and fate of IMP. Formation of IMP is catalyzed by the enzyme hypoxanthine/guanine phosphoribosyl tranfer-ase (1) from the substrate hypoxanthine (Hypo) and phosphoribosyl pyrophosphate (PRibPP). IMP is shown undergoing several reactions the first (2) is catalyzed by 5 -nucleotidase to form inosine (INO) and orthophosphate (Pj) the other (3) is a two-step reaction catalyzed by sAMP synthetase to form adenylosuccinate (sAMP) and (4) by the enzyme sAMP lyase to convert sAMP to AMP and fumarate. Finally, (3) the deamination of AMP to IMP and NHa is catalyzed by AMP deaminase.

Two enzyme abnormalities resulting in an overproduction of uric acid have been well described (Fig. 91-1). The first is an increase in the activity of phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased concentration of PRPP. PRPP is a key determinant of purine synthesis and thus uric acid production. The second is a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT). 

Quinolinic acid phosphoribosyl transferase (PT) catalyzes the formation of nicotinic acid mononucleotide (NaMN) from quinolinic acid and phosphoribosyl pyrophosphate. The pyridine nucleotide NaMN reacts with ATP (adenosine Hiphos-phate) upon mediation of NaMN adenylyltransferase to form the nicotinic acid adenine dinucleotide (NaAD) (Figure 6.7). The latter is converted to NAD by NAD synthetase. NADP is formed from NAD by the catalysis of NAD kinase. 

Phosphoribosyl-1-pyrophosphate synthetase 2 aminophosphoribosyltransferase 3 phospho-ribosylglycinamide synthetase 4 glycinamide ribonucleotide transformylase 5 iV-formylglycin-amidine ribonucleotide amidoligase 6 5-aminoimidazole ribonucleotide synthetase 7 5-amino-imidazole ribonucleotide carboxylase 8 5-aminoimidazole-4-iV-succinocarboxamide ribonucleotide synthetase 9 adenylosuccinate lyase 10 5-aminoimidazole-4-carboxamide ribonucleotide transformylase 11 inosinicase... 

The atoms of the pyrimidine ring are derived from carbamoyl phosphate and aspartate, as shown in Fig. 15-14. The de novo biosynthesis of pyrimidine nucleotides is shown in Fig. 15-15. The first completely formed pyrimidine ring is that of dihydroorotate. Only after oxidation to orotate is the ribose attached to produce orotidylate. The compound 5-phosphoribosyl 1-pyrophosphate (P-Rib-PP) provides the ribose phosphate. L-Glutamine is used as a substrate donating nitrogen atoms at reactions 1 and 9, catalyzed by carbamoyl phosphate synthetase II and CTP synthetase, respectively a second... 

Fig. 15-16 The de novo purine biosynthetic pathway. Rib-5-P, ribose 5-phosphate P-Rib-PP, 5-phosphoribosyl 1-pyrophosphate PRA, 5-phosphoribosylamine IO-CHO-FH4, /Vl0-formyl tetrahydrofolate GAR, glycineamide ribotide FGAR. /V-formylglycineamide ribotide FGAM, /V-formylglycineamidine ribotide AIR, 5-aminoimidazole ribotide CAIR, 4-carboxy-5-aminoimidazole ribotide SAICAR, iV-succino-5-aminoimidazole-4-carboxamide ribotide AICAR, 5-aminoimidazole-4-carboxamide ribotide FAICAR, 5-formamidoimidazole-4-carboxamide ribotide sAMP, /V-succino-AMP. Enzymes (1) amido phosphoribosyltransferase (2) GAR synthetase (3) GAR transformylase (4) FGAM synthetase (5) AIR synthetase (6) AIR carboxylase (7) SAICAR synthetase (8) adenylosuecinase (9) AICAR transformylase (10) IMP cyclohydrolase (11) sAMP synthetase (12) adenylosuecinasc (13) IMP dehydrogenase (14) GMP synthetase.

In the enzyme catalysis of the first committed step in the de novo synthesis of purines, an amino group from L-glutamine is transferred to 5-phosphoribosyl-l-pyrophosphate to form glutamate and 5-phosphoribosyl-1-amine. The assay includes glycinamide ribonucleotide synthetase, which converts 5-phosphoribosyl-l-amine to glycinamide ribonucleotide, which is the reaction product quantitated. 

Phosphoribosyl-l-pyrophosphate (PRPP) synthesis is catalyzed by PRPP synthetase. Note the ribose-5-phosphate for the pathway comes from tlie Pentose Phosphate Pathway (see "PPP/Gluconeogenesis" Lecture). 

In the human, nicotinic acid reacts with 5-phosphoribosyl-I-pyrophosphate to form nicotinic acid mononucleotide, which then reacts with ATP to produce desamido-NADIthc intermediate dinucleotide with the nicotinic acid moiety). Finally, the latter intermediate is converted to NAD (originally called coenzyme I) by transformation of the emboxyl of the nicotinic acid moiety to the amide by glutamine. Thb final step is catalyzed by NAD synthetase NADP is produced from NAD by ATT under kinase catalysis. ... 

---