Phosphoribosylamine phosphate

Figure 20.10 The positions in the pathway for de novo purine nucleotide synthesis where GLUCOSE provides the ribose molecule and GLUTAMINE provides nitrogen atoms. The pathway begins with glucose which provides ribose 5-phosphate, via the pentose phosphate pathway (Chapter 6). Glutamine provides its amide nitrogen in two reactions formation of 5-phosphoribosylamine and formation of guanosine monophosphate (GMP) from xantho-sine 5-phosphate (XMP).

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.

The first reaction proceeds by phosphorylation of glycine to form an acyl phosphate followed by nucleophilic attack by the amine of phosphoribosylamine to displace orthophosphate. The second reaction consists of adenylation of the carbonyl group of xanthylate followed by nucleophilic attack by ammonia to displace AMP. 

Its action is very complex, and a little of it, after bio-transformation to thioguanidylic acid, is incorporated into cellular DNA (Tidd and Paterson, 1974 Parks et al., 1975). However, it is not established that this is a therapeutically important reaction. Much of it is converted, in the cell, into 6-thioinosine 5 -phosphate (TIP) (Brockman, 1963). TIP inhibits conversion of inosine 5 -phosphate to adenosine 5 -phosphate, thus bringing neogenesis of purines to a halt (Salser and Balis, 1965). It also exerts feedback inhibition of the biosynthesis of phosphoribosylamine, a carbohydrate involved in the earliest steps in purine biosynthesis (Bennett etaL, 1963). 

Phosphoribosyl-l-pyrophosphate (PRPP) may be considered a precursor in the de novo sjmthetic reactions of purines, since this ribose derivative was required for the formation of 5-phosphoribosylamine (PRA). PRA was the precursor of nitrogen 9, ribose, and phosphate of the completed purine nucleotide structure (Section II, B, 1). PRPP was also a key substance in the biosynthesis of pyrimidine nucleotides. This compound was formed from ribose 5-phosphate and ATP by a pyrophosphorylation of carbon 1 of ribose 5-phosphate (78-80). This was an unusual kinase reaction in that pyrophosphate was transferred rather than phosphate as was the case with most kinases. The ribose 5-phosphate required for the syntheas of PRPP probably originated from glucose, and was formed either by an oxidative pathway from glucose 6-phosphate via 6-pho hogluconate and ribulose 5-phosphate (81) or anaerobically from fructose 6-pho hate (88). The formation of PRPP is shown in Fig. 4. 

The synthesis of purines de novo was initiated by the formation of 5-phosphoribosylamine by reaction of glutamine with 6-phosphoribosylpyro-phosphate. The latter compound was the product of reaction of ribose 5-... 

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