Abnormal Purine Metabolism and Purine Overproduction in a Patient Deficient in Purine Nucleoside Phosphorylase

Cohen, Amos; Doyle, Deborah; Martin, David W.; Ammann, Arthur J.

doi:10.1056/nejm197612232952603

Cited by 168 publications

(65 citation statements)

References 16 publications

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“…3 patients with a history of gout with normal HPRT levels on allopurinol therapy, 1 child with purine nucleoside phosphorylase deficiency, and 1 patient with PP-ribose-P synthetase overactivity. The latter two disorders have both been associated with purine overproduction (7,8). Z-nucleotides were not detected in extracts from normal individuals or from individuals on allopurinol therapy (Table I).…”

Section: Methodsmentioning

confidence: 99%

Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.

Sidi¹,

Mitchell²

1985

J. Clin. Invest.

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5-Amino4-imidazolecarboxamide riboside 5'-monophosphate (ZMP) is an intermediate in the purine de novo synthetic pathway that may be further metabolized to inosine 5'-monophosphate, degraded to the corresponding nucleoside (5-amino4-imidazolecarboxamide riboside; Z-riboside), or phosphorylated to the corresponding 5'-triphosphate (ZTP). Accumulation of ZTP in microorganisms has been associated with depletion of folate intermediates that are necessary for the conversion of ZMP to inosine 5'-monophosphate and has been postulated to play a regulatory role in cellular metabolism. We have shown the presence of Z-nucleotides in erythrocytes derived from five individuals with the Lesch-Nyhan syndrome. Erythrocyte folate levels were within the normal range, although guanosine triphosphate levels were significantly reduced below those in normal controls (P < 0.01). A small amount of Z-nucleotide accumulation was also found in one individual with partial deficiency of the enzyme hypoxanthine guanine phosphoribosyltransferase and in two individuals with other disorders of purine overproduction. In contrast, no Z-nucleotides were detected in 13 normal controls or in three individuals with hyperuricemia on allopurinol therapy. We conclude that Z-nucleotide formation may result from markedly increased rates of de novo purine biosynthesis. It is possible that metabolites of these purine intermediates may play a role in the pathogenesis of the Lesch-Nyhan syndrome.

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Section: Methodsmentioning

confidence: 99%

Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.

Sidi¹,

Mitchell²

1985

J. Clin. Invest.

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“…These conditions were accompanied by the accumulation, in plasma, of deoxyadenosine and deoxyguanosine, respectively (Cohen et al, 1976). This apparent selective toxicity to lymphocytes was characterized by the accumulation of the respective deoxynucleotide triphosphates, dATP and dGTP (Cohen et al, 1978a, b;Chan, 1978).…”

Section: Actions Of Nucleoside Analogs In Quiescent Cellsmentioning

confidence: 99%

Mechanisms of apoptosis induction by nucleoside analogs

2003

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Nucleoside analogs are structurally, metabolically, and pharmacodynamically related agents that nevertheless have diverse biological actions and therapeutic consequences. This class of agents affects the structural integrity of DNA, generally after incorporation during replication or DNA excision repair synthesis, leading to stalled replication forks and chain termination. The DNA damage sensors ATM, ATR and DNA-PK recognize these events. These and other protein kinases activate checkpoint pathways that arrest cell cycle progression, and also signal for DNA repair. In addition, if these survival mechanisms are overwhelmed by the damage caused, a third function of these sensors is to activate signaling pathways that initiate apoptotic processes. A review of the spectrum of responses that are activated by clinically relevant nucleoside analogs begins to provide a mechanistic basis for diverse outcomes in cell viability. Such information, when coupled with an understanding of the intrinsic apoptotic potential of a tumor cell type may provide a rational basis for the design of therapeutic strategies.

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“…Inherited deficiency of the enzyme purine nucleoside phosphorylase (PNP,' EC 2.4.2.1) is associated with severely impaired cellular immune function (1)(2)(3). In contrast, the more common adenosine deaminase (ADA, EC 3.5.4.4) deficiency causes a combined immune deficiency with marked reduction in both humoral and cellular immunity (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…These bases may then either be salvaged by hypoxanthine guanine phosphoribosyltransferase (HGPRTase) to ribonucleotides or further catabolized to uric acid. All four PNP precursors have been shown to be present at high levels in the urine of PNP-deficient individuals, with elevation of plasma inosine and guanosine and mild hypouricemia (3).…”

Section: Introductionmentioning

confidence: 99%

Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts.

Mann¹,

Fox²

1986

J. Clin. Invest.

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The mechanism by which 2'-deoxyguanosine is toxic for lymphoid cells is relevant both to the severe cellular immune defect of inherited purine nucleoside phosphorylase (PNP) deficiency and to attempts to exploit PNP inhibitors therapeutically. We have studied the cell cycle and biochemical effects of 2'-deoxyguanosine in human lymphoblasts using the PNP inhibitor 8-aminoguanosine. We show that cytostatic 2'-deoxyguanosine concentrations cause Gj-phase arrest in PNP-inhibited T lymphoblasts, regardless of their hypoxanthine guanine phosphoribosyltransferase status. This effect is identical to that produced by 2'-deoxyadenosine in adenosine deaminase-inhibited T cells. 2'-Deoxyguanosine elevates both the 2'-deoxyguanosine-5'-triphosphate (dGTP) and 2'-deoxyadenosine-5'-triphosphate (dATP) pools; subsequently pyrimidine deoxyribonucleotide pools are depleted. The time course of these biochemical changes indicates that the onset of GI-phase arrest is related to increase of the dATP rather than the dGTP pool. When dGTP elevation is dissociated from dATP elevation by coincubation with 2'-deoxycytidine, dGTP does not by itself interrupt transit from the GI to the S phase.

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Abnormal Purine Metabolism and Purine Overproduction in a Patient Deficient in Purine Nucleoside Phosphorylase

Cited by 168 publications

References 16 publications

Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.

Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.

Mechanisms of apoptosis induction by nucleoside analogs

Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts.

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