Purine products

The amino group now provides the nucleus for purine ring formation, an extended series of reactions we shall not describe. The first-formed purine product is inosine 5 -phosphate (IMP), which leads to either AMP or GMP these require amination at alternative sites, and utilize either GTP- or ATP-dependent reactions for amination. GTP or ATP (as appropriate) will also be required for further phosphorylations to produce the nucleotide triphosphates. 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

Trimethoprim- sulfamethoxazole Synergistic combination of folate antagonists blocks purine production and nucleic acid synthesis Bactericidal activity against susceptible bacteria Urinary tract infections Pneumocystis jiroveci pneumonia toxoplasmosis nocardiosis Oral, IV renal clearance (half-life 8 h) dosed every 8-12 h t formulated in a 5 1 ratio of sulfamethoxazole to trimethoprim Toxicity Rash, fever, bone marrow suppression, hyperkalemia... 

Purines. Product studies on the reactions of OH with the purines are not at the same level as those of the pyrimidine series. Only the products that can be traced back to an OH-attack at C(8) and involve the sugar moiety were detected with the presently available analytical techniques. Yet, OH attack at C(8) is only around 17% in Guo/dGuo and -30% in Ado/dAdo (see above). Attack at the... 

Table 12.13. Product ratios of typical purine products formed by the reaction of OH (y-radiolysis) and by H2O2 in 02-containing solution...

These enzymes are deactivated upon reaction with cyanide. Reactivation requires a source of sulfur, typically sulfide. Xn, xanthine or other purine substrates XnO, uric acid or other purine products. 

Fig. 41.2. Overview of purine production, starting with glutamine, ribose 5-phosphate, and ATP. The steps that require ATP are also indicated in this figure. RR = ribonucleotide reductase. FH4 = tetrahydrofolate. PRPP = 5-phosphoribosyl 1-pyrophosphate.

Sperling, O., Boer, P., Persky-Brosh, S., Kanarek, E., and De Vries, A., Altered kinetic property of erythroc e phosphoribosylpyrophosphate synthetase in excessive purine production, flee. Eur. Etud. Clin. Biol 17, 703-706 (1972). 

A common property of all Bacillus purine production strains is their aux-otrophy for adenine caused by a dysfunctional adenylosuccinate synthase gene (purA) of the AMP-specific branch of the purine pathway. Furthermore, the... 

Previous attempts to address this problem have shown no increase in specific activity of PRPP synthetase or amidophosphoribosyitransferase under conditions of stimulation of purine production (6). But in these studies enzyme assays were conducted under activating conditions in the assay cuvette. The present study (10) demonstrates that marked changes of enzyme activity can be brought about in vivo by allosteric effects that would not be detected by routine assays and that require conditions which allow recognition of the physical and catalytic state of the enzyme in the tissue at the moment of analysis. 

Increases in rates of purine production could in theory result from increased concentrations of the substrates PP-ribose-P or glutamine, increased activity of the amidotransferase, or decreased availability or non-optimal ratios of feedback inhibitors [39,46]. 

Sperling, 0., P. Boer, S. Persky-Brosh, E. Kanarek, and A. de Vries. 1972. Altered kinetic property of erythrocyte phosphoribosylpyrophosphate synthetase in excessive purine production. Europ. J. Clin. Biol. Res. 17 703. 

The Lesch-Nyhan Syndrome (LNS) is a rare x-linked neurological disease of children characterized by choreoathetosis, spasticity, mental retardation and compulsive self mutilation accompanied by excessive purine production and hyperuricemia (l). The virtually complete deficiency of activity of a purine salvage enzyme, hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) (EC 2.4.2.8.) (2), due to structural gene mutation (3 4) has been shown to be the basic abnormality in this disease. In erythrocytes of LNS patients, HGPRT deficiency has been found to be associated with increased activity and relative thermal stability of adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7 ) (5 6) an autosomally determined enzyme (7) ... 

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