Purines intracellular formation

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

Increased levels of intracellular PRPP enhance de novo purine biosynthesis. For example, in patients with HPRT deficiency, the fibroblasts show accelerated rates of purine formation. Several mutations of PRPP synthetase, which exhibit increased catalytic activity with increased production of PRPP, have been described in gouty subjects. 

The hyperuricemia in Lesch-Nyhan patients is explained, at least in part, on the basis of intracellular accumulation of PRPP leading to increased purine nucleotide biosynthesis de novo and increased production of uric acid. Such patients do not usually develop gouty arthritis early in life but do exhibit uric acid crystalluria and stone formation. 

The formation of IMP may provide a means by which the intracellular purine nucleotide pool is maintained. AMP deaminase deficiency disrupts the purine... 

Approximately 80% of red blood cell purines are in the form of adenosine triphosphate (ATP) with an intracellular concentration estimated to be 2-3 mM. In glucose-deprived or aged red cells there is a progressive decline in the ATP content of the erythrocyte leading to the formation of adenosine diphosphate (ADP) and adenosine monophosphate (AMP) AMP is then dephosphorylated (via 5 -nucleotidase) to... 

IMP v/hich was always the main labeled compound present within erythrocytes). After the lag time, the rate of hypoxanthine release was about the same of that observed in the absence of formycin B (fig. 2). Since, at the concentration employed, formycin B is known to inhibit purine nucleoside phosphorylase in intact human erythrocytes, these results confirm that the cells sequentially degrade the intracellular IMP to inosine and hypoxanthine and suggest that the phosphory-lase-catalyzed formation of hypoxanthine from its nucleoside is not the rate limiting step in this catabolic path. 

Allopurinol therapy results in the accumulation of the purine bases, hypoxanthine and xanthine and probably also leads to an increased formation of their ribonucleotide derivatives. The effect of these compounds along with the 1-N ribonucleotide derivative of allopurinol (supplied by Dr. Gertrude B. Elion, Burroughs Wellcome) on OPRT and ODC was examined in vitro. Xanthosine-5-monophosphate (XMP) and allopurinol ribonucleotide were found to be competitive inhibitors of ODC (Table 1) with Ki s of 7 X 10" M and 8 X 10" M respectively (Kelley and Beardmore, 1970). This suggested that the inhibition of ODC vivo might be due to an accumulation of allopurinol and xanthine with a consequent increase in the intracellular concentration of their ribonucleotide derivatives. However, the findings that oxipurinol was a more effective inhibitor than allopurinol and that the inhibition in vivo was not... 

The administration of allopurinol at a dose ranging from 2 to 4 mg/Kg to 9 patients with normal hypoxanthine-guanine phosphor-ibosyltransferase (HGPRT) led to a significant reduction in intracellular PP-ribose-P levels with a maximum decrease to a mean of 47% of control values observed within three to five hours (Fig. 3). Allopurinol also depleted intracellular PP-ribose-P levels in vitro in intact erythrocytes with normal HGPRT. Additional studies have demonstrated that the depletion of PP-ribose-P produced by allopurinol is due to the conversion of allopurinol to its ribonucleotide, a process which utilizes PP-ribose-P. The depletion of intracellular PP-ribose-P and the formation of allopurinol ribonucleotide, a known inhibitor of PP-ribose-P amidotransferase, may both contribute to the decreased rate of purine biosynthesis de novo commonly observed in patients on allopurinol therapy. 

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