Purine and pyrimidine metabolism

Zöllner, N.

doi:10.1079/pns19820048

Cited by 50 publications

(31 citation statements)

References 25 publications

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“…Purines can be generated de novo or they can be recycled from sources within the body through a 'salvage pathway' Zollner, 1982). De novo synthesis starts with the precursor 5-phospho-D-ribosyl-1-pyrophosphate (PRPP) and this is converted to inosine monophosphate (IMP) through ten enzymatic steps (Fig.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish mutations ingartandpaicsidentify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

Uribe

Yieh

et al. 2009

Development

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Although purines and purinergic signaling are crucial for numerous biochemical and cellular processes, their functions during vertebrate embryonic development have not been well characterized. We analyze two recessive zebrafish mutations that affect de novo purine synthesis, gart and paics. gart encodes phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase, a trifunctional enzyme that catalyzes steps 2, 3 and 5 of inosine monophosphate (IMP) synthesis. paics encodes phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase, a bifunctional enzyme that catalyzes steps 6 and 7 of this process. Zygotic gart and paics mutants have pigmentation defects in which xanthophore and iridophore pigmentation is almost completely absent, and melanin-derived pigmentation is significantly decreased, even though pigment cells are present in normal amounts and distributions. Zygotic gart and paics mutants are also microphthalmic, resulting from defects in cell cycle exit of proliferative retinoblasts within the developing eye. Maternal-zygotic and maternal-effect mutants demonstrate a crucial requirement for maternally derived gart and paics; these mutants show more severe developmental defects than their zygotic counterparts. Pigmentation and eye growth phenotypes in zygotic gart and paics mutants can be ascribed to separable biosynthetic pathways: pigmentation defects and microphthalmia result from deficiencies in a GTP synthesis pathway and an ATP synthesis pathway, respectively. In the absence of ATP pathway activity, S phase of proliferative retinoblasts is prolonged and cell cycle exit is compromised, which results in microphthalmia. These results demonstrate crucial maternal and zygotic requirements for de novo purine synthesis during vertebrate embryonic development, and identify independent functions for ATP and GTP pathways in mediating eye growth and pigmentation, respectively.

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Section: Introductionmentioning

confidence: 99%

Zebrafish mutations ingartandpaicsidentify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

Uribe

Yieh

et al. 2009

Development

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“…Nucleosides are essential components of DNA and RNA, the genomic memory devices, and also play pivotal roles as energy sources and in signal transductions (1,2). In mammals, nucleosides can be synthesized via the de novo pathway from small precursor molecules, such as aspartate, glutamine, glycine, and 10-formyltetrahydrofolate, and via the salvage pathway from nucleobases.…”

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confidence: 99%

Identification and Functional Characterization of the First Nucleobase Transporter in Mammals

Yamamoto

Inoue

Murata

et al. 2010

Journal of Biological Chemistry

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Nucleobases are important compounds that constitute nucleosides and nucleic acids. Although it has long been suggested that specific transporters are involved in their intestinal absorption and uptake in other tissues, none of their molecular entities have been identified in mammals to date. Here we describe identification of rat Slc23a4 as the first sodiumdependent nucleobase transporter (rSNBT1). The mRNA of rSNBT1 was expressed highly and only in the small intestine. When transiently expressed in HEK293 cells, rSNBT1 could transport uracil most efficiently. The transport of uracil mediated by rSNBT1 was sodium-dependent and saturable with a Michaelis constant of 21.2 M. Thymine, guanine, hypoxanthine, and xanthine were also transported, but adenine was not. It was also suggested by studies of the inhibitory effect on rSNBT1-mediated uracil transport that several nucleobase analogs such as 5-fluorouracil are recognized by rSNBT1, but cytosine and nucleosides are not or only poorly recognized. Furthermore, rSNBT1 fused with green fluorescent protein was mainly localized at the apical membrane, when stably expressed in polarized Madin-Darby canine kidney II cells. These characteristics of rSNBT1 were almost fully in agreement with those of the carrier-mediated transport system involved in intestinal uracil uptake. Therefore, it is likely that rSNBT1 is its molecular entity or at least in part responsible for that. It was also found that the gene orthologous to the rSNBT1 gene is genetically defective in humans. This may have a biological and evolutional meaning in the transport and metabolism of nucleobases. The present study provides novel insights into the specific transport and metabolism of nucleobases and their analogs for therapeutic use.Nucleosides are essential components of DNA and RNA, the genomic memory devices, and also play pivotal roles as energy sources and in signal transductions (1, 2). In mammals, nucleosides can be synthesized via the de novo pathway from small precursor molecules, such as aspartate, glutamine, glycine, and 10-formyltetrahydrofolate, and via the salvage pathway from nucleobases. In the salvage pathway, the supply of nucleobases mainly occurs from extracellular sources, typically those produced by digestion of dietary nucleic acids in the intestinal lumen. There also occurs redistribution of nucleosides/nucleobases via bloodstream from the tissues that are highly active in de novo synthesizing and/or degrading nucleosides. Therefore, carrier-mediated transport systems are needed for the efficient trafficking across cellular membranes of nucleosides and nucleobases, which are hydrophilic and hence can little permeate otherwise (3, 4).The transporters involved in the cellular uptake of nucleosides have been well characterized in mammals, including humans (5-7). There are two families of transporters, which are sodium-coupled concentrative nucleoside transporters (CNT1/SLC28A1, CNT2/SLC28A2, and CNT3/SLC28A3) and equilibrative nucleoside transporters (ENT1/SLC29A1 and ENT2/SLC29A2...

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“…Adenosine is a major purine nucleoside of human blood, but the adenosine kinase activity of P. falciparum is very low (9). Adenosine deaminase is very active in the erythrocyte and the parasite; hence deamination and subsequent phosphorolysis of the product inosine by PNP 1 yield hypoxanthine, a major purine precursor for purine salvage (Fig.…”

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confidence: 99%

Purine-less Death in Plasmodium falciparumInduced by Immucillin-H, a Transition State Analogue of Purine Nucleoside Phosphorylase

Kicska¹,

Tyler²,

Evans³

et al. 2002

Journal of Biological Chemistry

120

151

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Plasmodium falciparum is responsible for the majority of life-threatening cases of malaria. Plasmodia species cannot synthesize purines de novo, whereas mammalian cells obtain purines from de novo synthesis or by purine salvage. Hypoxanthine is proposed to be the major source of purines for P. falciparum growth. It is produced from inosine phosphorolysis by purine nucleoside phosphorylase (PNP) Malaria is caused by the protozoan parasites Plasmodium falciparum, ovale, vivax, and malariae and is responsible for an estimated 1-2 million deaths per year (1, 2). Controlling this disease with current anti-malarials has become more difficult because of emerging drug-resistant strains (1, 2). Therefore, the validation of alternative anti-malarial targets is crucial to development of new chemotherapeutic approaches. The purine salvage pathway has been identified as a potential anti-malarial target (3, 4). Unlike its host, Plasmodium cannot synthesize purines de novo and depends exclusively on purine salvage for RNA and DNA synthesis (3, 5-8). Erythrocytes also lack enzymes for de novo purine synthesis. The parasite requires a continuous supply of purines for RNA and DNA synthesis during its replication in the erythrocyte..Adenosine is a major purine nucleoside of human blood, but the adenosine kinase activity of P. falciparum is very low (9). Adenosine deaminase is very active in the erythrocyte and the parasite; hence deamination and subsequent phosphorolysis of the product inosine by PNP 1 yield hypoxanthine, a major purine precursor for purine salvage (Fig. 1). There is no adenosine phosphorylase activity in humans, and adenine is present at very low concentrations (10). Hypoxanthine is converted to IMP by hypoxanthine phosphoribosyltransferase activity, present in large amounts in P. falciparum (11). This path makes hypoxanthine the common precursor for all purine nucleotides in the parasite (12). Depleting Plasmodium of hypoxanthine by the addition of xanthine oxidase to culture medium prevents parasite growth (13,14). This mechanism has also evolved in vivo in the cape buffalo, where resistance to Trypanosoma brucei infections has resulted from an active serum xanthine oxidase (15).In mammals, hypoxanthine is formed from nucleosides only through phosphorolysis of inosine, the reaction catalyzed by PNP. Here we test the hypothesis that inhibition of purine nucleoside phosphorylase in infected erythrocytes will inhibit P. falciparum growth by preventing hypoxanthine production. This goal is possible through the use of transition state analogue inhibitors we have developed against both human and P. falciparum PNPs (16,17). The immucillins are purine nucleoside analogue inhibitors containing a 1-(9-deazapurin-9-yl)-1,4-dideoxy-4-iminoribitol moiety (Fig. 2). Inhibition of both human and P. falciparum PNP by immucillins prevents the utilization of inosine and deoxyinosine as hypoxanthine sources. P. falciparum parasites cultured in human erythrocytes are killed by immucillins but can be rescued by hypoxanthine and not ...

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Purine and pyrimidine metabolism

Cited by 50 publications

References 25 publications

Zebrafish mutations ingartandpaicsidentify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

Zebrafish mutations ingartandpaicsidentify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

Identification and Functional Characterization of the First Nucleobase Transporter in Mammals

Purine-less Death in Plasmodium falciparumInduced by Immucillin-H, a Transition State Analogue of Purine Nucleoside Phosphorylase

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