Phosphoribosyl group

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. 

There are many transferases catalysing the transfer of a 5-phosphoribosyl group from 5 -ribosyl pyrophosphate to nitrogen, but detailed mechanistic studies are not available. All such enzymes, however, are activated by divalent cations such as Mg ", which coordinates to the pyrophosphate oxygens and increases leaving group ability. 

QUESTION 14.10 What is the source of the phosphoribosyl group of nucleotides What pathway... 

The source of the phosphoribosyl group of nucletotides is PRPP (5-phosphoribosyl-a-D-l-pyrophosphate). PRPP is generated from ribose-5-phosphate, a product of the pentose phosphate pathway. 

Fig.1 The reaction catalyzed by ODCase, showing the structure of a possible carbanion-ic intermediate formed during decarboxylation. R-5 -P represents a 5 -phosphoribosyl group...

Finally, the uracil phosphoribosyltransferase of beef erythrocytes recognizes the 2,4-dioxypyrimidine moiety of xanthine and uric acid, and attaches the phosphoribosyl group to the 3-position of these purines, as it is analogous with the N-1 of uracil. Uric acid 3-ribonucleoside is found as a constituent of beef erythrocytes, and presumably arises by dephosphorylation of the nucleotide derivative (48, 49). 

The hypE proteins are 302-376 residues long and appear to consist of three domains. Domain 1 shows sequence identity to a domain from phosphoribosyl-aminoimida-zole synthetase which is involved in the fifth step in de novo purine biosynthesis and to a domain in thiamine phosphate kinase which is involved in the synthesis of the cofactor thiamine diphosphate (TDP). TDP is required by enzymes which cleave the bond adjacent to carbonyl groups, e.g. phosphoketolase, transketolase or pyruvate decarboxylase. Domain 2 also shows identity to a domain found in thiamine phosphate kinase. Domain 3 appears to be unique to the HypF proteins. 

A common intermediate for all the nucleotides is 5-phosphoribosyl-l-diphosphate (PRPP), produced by successive ATP-dependent phosphorylations of ribose. This has an a-diphosphate leaving group that can be displaced in Sn2 reactions. Similar Sn2 reactions have been seen in glycoside synthesis (see Section 12.4) and biosynthesis (see Box 12.4), and for the synthesis of aminosugars (see Section 12.9). For pyrimidine nucleotide biosynthesis, the nucleophile is the 1-nitrogen of uracil-6-carboxylic acid, usually called orotic acid. The product is the nucleotide orotidylic acid, which is subsequently decarboxylated to the now recognizable uridylic acid (UMP). 

Attack at the /3 phosphate of ATP displaces AMP and transfers a pyrophosphoiyl (not pyrophosphate) group to the attacking nucleophile (Pig. 13-10b). For example, the formation of 5 -phosphoribosyl-1-pyrophosphate (p. XXX), a key intermediate in nucleotide synthesis, results from attack of an —OH of the ribose on the /3 phosphate. 

A useful way to organize these biosynthetic pathways is to group them into six families corresponding to their metabolic precursors (Table 22-1), and we use this approach to structure the detailed descriptions that follow. In addition to these six precursors, there is a notable intermediate in several pathways of amino acid and nucleotide synthesis—5-phosphoribosyl-l-pyrophosphate (PRPP) ... 

Phosphoribosyl pyrophosphate (PRPP) is important in both, and in these pathways the structure of ribose is retained in the product nucleotide, in contrast to its fate in the tryptophan and histidine biosynthetic pathways discussed earlier. An amino acid is an important precursor in each type of pathway glycine for purines and aspartate for pyrimidines. Glutamine again is the most important source of amino groups—in five different steps in the de novo pathways. Aspartate is also used as the source of an amino group in the purine pathways, in two steps. 

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). 

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. 

At this stage, orotate couples to ribose, in the form of 5-phosphoribosyl-l-pyrophosphate (PRPP), a form of ribose activated to accept nucleotide bases. PRPP is synthesized from ribose-5-phosphate, formed by the pentose phosphate pathway, by the addition of pyrophosphate from ATP. Orotate reacts with PRPP to form orotidylate, a pyrimidine nucleotide. This reaction is driven by the hydrolysis of pyrophosphate. The enzyme that catalyzes this addition, pyrimidine phosphoribosyltransferase, is homologous to a number of other phosphoribosyltransferases that add different groups to PRPP to form the other nucleotides. Orotidylate is then decarboxylated to form uridylate (IMP), a major pyrimidine nucleotide that is a precursor to RNA. This reaction is catalyzed by orotidylate decarboxylase. 

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