Ribosyl 5-0-phospho

Phosphoribosylpyrophosphate (PRPP) synthetase is one of the very few enzymes which transfer a pyrophosphoryl group from ATP in one step. When the synthesis is carried out in lsO-enriched water, lsO is incorporated into the PRPP, but not into AMP.91 The lsO in the PRPP arises from a pre-exchange between the H2180 and the ribose phosphate, and hence the results confirm that fission of the /5-P—O bond takes place. PRPP and ATP are starting materials in the biosynthesis of histidine, and Ai-(5 -phospho-D-ribosyl)adenosine triphosphate (29) is an intermediate. The... 

Figure 20.9 The positions in the pathway for de novo pyrimidine nucleotide synthesis where GLUCOSE provides the ribose molecule and GLUTAMINE provides nitrogen atoms. Glucose forms ribose 5-phosphate, via the pentose phosphate pathway (see chapter 6), which enters the pathway, after phosphorylation, as 5-phospho-ribosyl 1-pyrophosphate. Glutamine provides the nitrogen atom to synthesise carbamoylphos-phate (with formation of glutamate), and also to form cytidine triphosphate (CTP) from uridine triphosphate (UTP), catalysed by the enzyme CTP synthetase. It is the amide nitrogen of glutamine that is the nitrogen atom that is provided in these reactions.

The second example in Figure 11.2 shows guanine bound to a phospho-ribosyl transferase. Only one of the two possible tautomers is able to form the correct hydrogen bond to an active site aspartate. 

Fig. 11.2 Guanine bound to a phospho-ribosyl transferase (PDB la95).

This enzyme [EC 2.4.2.18], also referred to as phospho-ribosyl-anthranilate pyrophosphorylase, catalyzes the reaction of anthranilate with phosphoribosylpyrophos-phate to produce A-5 -phosphoribosylanthranilate and pyrophosphate. In certain species, this enzyme is part of a multifunctional protein, together with one or more other components of the system for the biosynthesis of tryptophan (i.e., indole-3-glycerol-phosphate synthase, anthranilate synthase, tryptophan synthase, and phos-phoribosylanthranilate isomerase). 

This enzyme [EC 2.4.2.17], also known as phosphoribo-syl-ATP pyrophosphorylase, catalyzes the reaction of ATP with 5-phospho-a-D-ribose 1-diphosphate to generate l-(5-phospho-D-ribosyl)-ATP and pyrophosphate. 

This enzyme [EC 2.4.2.21] catalyzes the reaction of /3-nicotinate D-ribonucleotide with dimethylbenzimidazole to produce nicotinate and Af -(5-phospho-a-D-ribosyl)-5,6-dimethylbenzimidazole. Benzimidazole also serves as a substrate. The clostridial enzyme acts on adenine to produce 7-a-D-ribosyladenine 5 -phosphate. 

Fig. lA. Anabolic and catabolic pathways of 5-FU. DPD dihydropyrimidine dehydrogenase, DP di-hydropyrimidinase, pUP beta-ureidopropionase, UP uridine phosphorylase, OPRT orotate phospho-ribosyl transferase, UK uridine kinase, TP thymidine phosphorylase, TK thymidine kinase, RNR ribonucleotide reductase. The three active metabolites (shown in rectangles) are FdUMP (5-fluoro-2 -deoxyuridine 5 -monophosphate) inhibiting TS (thymidylate synthase), and FUTP (5-fluorouridine 5 -triphosphate) and FdUTP (5-fluoro 2 -deoxyuridine 5 -triphosphate) interfering with RNA and DNA, respectively. 

Hirsch, and A.W. Hsie. A quantitative assay of mutation induction at hypoxanthine-guanine phospho-ribosyl transferase locus in Chinese hamster ovary cells (CHO/HGPRT system) Development and definition of the system. Mutat. Res. 45 91-101, 1977. 

Serine (hydroxyl) phospho- glycosyl- methyl- phosphopantetheine- ADP-ribosyl 8... 

Escherichia coli B was incubated with 2,6-diaminopurine (XXIV), and 6-amino-2-(methylamino)-9-(5-0-phospho-D-ribosyl)purine (XXV) was isolated from the acid-soluble extract of the cells. 5-Nucleotidase liberated a nucleoside containing D-ribose. Hydrolysis of the nucleoside (or nucleotide) with N hydrochloric acid liberated 6-amino-2-(methylamino)purine, which was identified by paper chromatography and by its ultraviolet absorption spectrum. The chromatographic and ion-exchange behavior of the extract also suggested the presence of either a pyrophosphate or a triphosphate of the 6-amino-2-methylamino-(D-ribosyl)purine. In a similar manner, 2,6-diamino-9-(5-0-phospho-D-ribosyl)purine (XXVI) was isolated and identified, together with its possible pyrophosphate or triphosphate. 2,6-... 

It has been shown that an extract of Salmonella typhimwrium catalyzes the formation of 5-amino-l-(5-0-phospho-D-ribosyl)-4-imidazolecarboxa-mide (XXXII) according to the following sequence of reactions. ... 

The conversion of anthranilic acid to tryptophan by cell-free extracts involves, initially, a reaction with 5-0-phospho-a-D-ribosyl pyrophosphate (XX, see Fig. 8). On the basis of the known enzymic reactions of XX, the formation of X-(o-carboxyphenyl)- 9-D-ribofuranosylamine 5-phosphate (XXI) would be expected. However, the first identifiable compound is the unphosphorylated, Amadori-rearrangement product XXII which is formed... 

New purine bases are produced, at the nucleotide level, by the de novo biosynthetic route which commences with 5-phospho-a-D-ribosyl pyrophosphate and proceeds via 5-phospho-/3-D-ribosylamine to produce IMP in a sequence of enzyme-controlled reactions involving aminoimidazole intermediates. IMP is further converted into AMP and GMP by separate pathways (Scheme 157). 

Bl. Bakay, B., and Nyhan, W. L., Heterogeneity of hypoxanthine guanine phospho-ribosyl transferase from human erythrocytes. Arch. Biochem. Biophys. 168, 26-34... 

PURINE NUCLEOTIDES The de novo synthesis of purine nucleotides begins with the formation of 5-phospho-a-D-ribosyl- 1-pyrophosphate (PRPP) catalyzed by ribose-5-phosphate pyrophosphokinase (PRPP synthetase). 

Inosinic acid (1), the first nucleotide to be discovered, was isolated over a century ago from beef extract by Liebig. Mild, acid hydrolysis of this nucleotide yielded a ribose phosphate (2) which, by oxidation with nitric acid, gave a ribonic acid phosphate (3), but not a ribaric acid phosphate. These studies by Levene and his associates showed that the phosphoric (phospho) group is bound to the 5-hydroxyl group of the ribosyl moiety in 1 hence, inosinic acid is inosine 5 -phosphate. Adenylic acid (4), isolated from muscle, was converted enzymically (by adenylic... 

Nitro-6-hydrazino-4-hydroxy- 532 5-Nitro-5-methyl-1,3-dibenzyl-hexahydro- 504 2-Oxo-hexahydro- 315, 318 2-Oxo-4-mercapto- 1-methyl-1,2-dihydro- 318 2-Oxo-1-methyl-hexahydro- 318 5-Oxo-1,4,5.6-tetrahydro- 315, 317 5-Phenylazo-6-hydroxy-2,4-dimethyl- 553 1 - (5-O- Phospho-/ - d-ribosyl)- 4-hydroxy- 2-oxo-... 

Figure 6 Amadori rearrangements catalyzed by HisA [A/-(5 -phospho-L-ribosyl-formimino)-5-amino-1 -(5 -phosphoribosyl)-4-imidazolecarboxamide isomerase] and TrpF (phosphoribosylanthranilate isomerase).

Phospho-ot-D-ribosyl-l-pyrophosphate (PRPP) is an intermediate in both the de novo synthesis of nucleotides (Figure 22.1) and the salvage synthesis (reutilization) of nucleotides (Figure 22.2). 

Guanine phospho-ribosyl transferase n 6/4/52 [xM (IC50) Aronov, A.M. et at, Antimicr. Agents Chemother. 2001, 45,2571. 

Initially, the Cj position of the ribose-5-phosphoric acid (ribose-5-phosphate) unit is activated by phosphorylation with ATP, and it becomes 5-phospho-D-ribosyl-l-pyrophosphoric acid (PRPP).This pyrophospho-ric acid unit is replaced with an activated ammonia derived from a glutamine with inversion of the stereoconfiguration at the Cj position. It is this nitrogen atom that subsequently becomes N-9 of the purine base. 

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