Phosphoribosyl pyrophosphate reactions

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 2.4.2.14], also known as glutamine phosphoribosyl-pyrophosphate amidotransferase, catalyzes the reaction of glutamine with S-phospho-a-D-ri-bose 1-diphosphate and water to produce 5-phospho-)3-D-ribosylamine, diphosphate (or, pyrophosphate), and glutamate. 

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. 

During the conversion of anthranilate to tryptophan, two additional carbon atoms must be incorporated to form the indole ring. These are derived from phosphoribosyl pyrophosphate (PRPP) which is formed from ribose 5-phosphate by transfer of a pyro-phospho group from ATP.60 61 The - OH group on the anomeric carbon of the ribose phosphate displaces AMP by attack on Pp of ATP (Eq. 25-5). In many organisms the enzyme that catalyzes this reaction is fused to subunit II of anthranilate synthase.62 PRPP is also the donor of phosphoribosyl groups for biosynthesis of histidine (Fig. 25-13) and of nucleotides (Figs. 

The trinucleotide ZTP also accumulates, not only in bacteria but also in many eukaryotic cells. Bochner and Ames suggested it may be an alarmone signaling a deficit of folate coenzymes in the cell and causing a shutdown of protein synthesis. ZTP is synthesized by an unusual reaction, transfer of a pyrophosphate group from PRPP (phosphoribosyl pyrophosphate). 

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.

In nucleotide synthesis, GMP is formed from phosphoribosyl pyrophosphate in the first reaction below catalyzed by a phosphoribosyl transferase ... 

Nicotinamide serves as the major precursor of NAD in mammalians. The reaction with phosphoribosyl pyrophosphate (PRPP) leads to the formation of nicodtiamide mononucleotide, NMN. Finally, this mononucleotide is linked to the adenylate moiety of ATP forming NAD (Fig. 2). This reaction is catalysed by nicotinamide mononucleotide adenylyltransferases, NMNATs. 

Pyrimidine biosynthesis commences with a reaction between carbamyl phosphate and aspartic acid to give carbamyl aspartic acid which then nndergoes ring closure and oxidation to orotic acid. A reaction then occurs between orotic acid and 5-phosphoribosyl pyrophosphate to give orotidine-5-phosphate which on decarboxylation yields uridine-5-phosphate (UMP). By means of two successive reactions with ATP, UMP can then be converted into UTP and this by reaction with ammonia can give rise to cytidine triphosphate, CTP (11.126). 

Huckel s method of molecular orbitals. II. Analogues of the orotic acid in the reaction with phosphoribosyl-pyrophosphate. J. Theor. Biol., 26, 29-32 (1970)... 

The 5-phosphoribo l group is transferred from phosphoribosyl pyrophosphate to a wide variety of nitrogenous compounds in several areas of metabolism these reactions are listed in Table 5-V. 

Studies on the biosynthesis of histidine in Salmonella by Ames and Hartman [214] established the simultaneous repression of several enzymes. In the series of reactions (at least 10 different steps) involved in the biosynthesis of the histidine molecule, the 5-carbon chain of phosphoribosyl pyrophosphate is converted to the 5-carbon chain of histidine. In Sal-... 

The reaction that catalyzes the conversion of ribosyl pyrophosphate to 5 -phosphoribosylamine is likely to be the rate-limiting step in purine biosynthesis. Of course, it is difficult to pinpoint a rate-limiting step in an intact mammal, but in vitro experiments have established a feedback inhibition of glutamine phosphoribosyl pyrophosphate amino transferase by adenylic and guanylic nucleotides (ATP, ADP, GMP, GDP, and IMP). 

There is not enough time and space to describe my early work on thiamine pyrophos-phokinase, but I would like to point out that the pyrophosphorylation is a reaction less common than either phosphorylation or adenylylation. So far, only three examples are known. The one first reported by A. Kornberg< > was the synthesis of phosphoribosyl pyrophosphate and the most recent one was the formation of ppGpp from ATP and GDP as demonstrated by Sy and Lipmann.< > I feel it no mere coincidence that I am now working a little on the role of this unusual nucleotide in the stringent control. 

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. 

The purine and pyrimidine bases can be converted to then-respective nncleotides by reaction with 5-phosphoribosyl 1-pyrophosphate. Since these bases are not very soluble, they are not transported in the blood, so that the reactions are only of qnantitative significance in the intestine, where the bases are produced by degradation of nucleotides. In contrast, in some cells, nucleosides are converted back to nucleotides by the activity of kinase enzymes. In particular, adenosine is converted to AMP, by the action of adenosine kinase, and uridine is converted to UMP by a uridine kinase... 

This enzyme [EC 3.6.1.31] catalyzes the hydrolysis of 5-phosphoribosyl-ATP to produce 5-phosphoribosyl-AMP and pyrophosphate (or, diphosphate). The Neurospora crassa enzyme also catalyzes the reactions of histidinol dehydrogenase and phosphoribosyl-AMP cyclohydrolase. 

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