The Source of Purines and Pyrimidines in Plasmodium Berghei *

K, Van Dyke; Gc, Tremblay; Ch, Lantz; Szustkiewicz, C.

doi:10.4269/ajtmh.1970.19.202

Cited by 69 publications

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“…Irvin and Young (1979) have demonstrated the incorporation of adenosine into nucleic acid by B. rodhaini. If this parasite resembles Plasmodium in requiring purines for nucleic acid synthesis (Van Dyke et al, 1970), then a purine nucleoside such as adenosine should be a required nutrient. But parasite survival in KRP medium was not increased by the addition of adenosine, despite its positive effect on AEC and ATP production.…”

Section: Discussionmentioning

confidence: 99%

METABOLISM OF BABESIA PARASITES IN VITRO. GLUCOSE AND ENERGY METABOLISM AND SURVIVAL OF BABESIA RODHAINI IN A BASAL MEDIUM WITH AND WITHOUT ADENOSINE

1982

Aust J Exp Biol Med

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Summary.During in vitro incubation in Krebs Ringer phosphate (KRP) medium, rat erythrocytes about 20% parasitized with B. rodhaini used two to four times as much gtucose as unparasitized erythrocytes. However, the ATP concentration and ATP production of parasitized erythrocytes decreased. For example, before incubation the ATP concentration in parasitized erythrocytes was significantly higher than unparasitized erythrocytes, but following 0-5 h incubation it was reduced to about the same as in unparasitized erythrocytes.Addition of 5 X 10-3 M adenosine to the basal medium increased the ATP production and the adenylate energy charge of parasitized erythrocytes. Infectivity tests in susceptible mice showed that, despite these seemingly favourable changes in energy metabolism, adenosine had no detectable effect on the survival of B. rodhaini. Absence of infectivity showed the inability of KRP medium to support B. rodhaini for 22 h in vitro with or without adenosine.Adenosine also greatly decreased the glucose uptake by parasitized erythrocytes, apparently by competitive inhibition, since lactate production was unchanged. INTRODUCTIONStudies of the metabolism of haemoprotozoan parasites of the genus Babesia are relevant to the production of living vaccines against bovine infections (Callow, 1977). The present series of investigations was designed to study the in vitro metabolism and survival in basal salts media of Babesia rodhaini.Metabolic studies of Babesia rodhaini (Rickard, 1969;Momen, 1979) provided information on the in vitro metabolism, particularly carbohydrate metabolism, of the parasite in basal salts media. There was no information, however, on the in vitro survival or energy metabolism of the parasite in basal media.

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Section: Discussionmentioning

confidence: 99%

METABOLISM OF BABESIA PARASITES IN VITRO. GLUCOSE AND ENERGY METABOLISM AND SURVIVAL OF BABESIA RODHAINI IN A BASAL MEDIUM WITH AND WITHOUT ADENOSINE

1982

Aust J Exp Biol Med

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“…This review will focus primarily on the purine salvage pathways present in the Plasmodium parasite. Recent reviews have examined the metabolic pathways for purine salvage in other protozoa (11,17,29).Initial studies on purine and pyrimidine synthesis in Plasmodium parasites were performed on erythrocytic stages of the rodent malaria species P. berghei (7,8,65), the macaque monkey malaria species P. knowlesi (46), and the avian malaria parasite P. lophurae (61,66 (46). Following on from these findings, Gutteridge and Trigg found that, in P. knowlesi, all radiolabeled purines were significantly incorporated into nucleic acids while none of the pyrimidines tested were (28).…”

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“…Initial studies on purine and pyrimidine synthesis in Plasmodium parasites were performed on erythrocytic stages of the rodent malaria species P. berghei (7,8,65), the macaque monkey malaria species P. knowlesi (46), and the avian malaria parasite P. lophurae (61,66). Work by Sherman and colleagues indicated a functional purine salvage pathway in P. lophurae (61,66 (7,8).…”

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“…Work by Sherman and colleagues indicated a functional purine salvage pathway in P. lophurae (61,66 (7,8). Van Dyke and colleagues showed that uptake and incorporation (into nucleic acid) occur for the purine adenosine but not for the pyrimidines uridine and cytidine and that adenosine is incorporated far more efficiently than adenine, guanosine, and deoxyadenosine (65 (46). Following on from these findings, Gutteridge and Trigg found that, in P. knowlesi, all radiolabeled purines were significantly incorporated into nucleic acids while none of the pyrimidines tested were (28).…”

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Purine Salvage Pathways in the Intraerythrocytic Malaria Parasite Plasmodium falciparum

2008

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2Malaria is caused by protozoan parasites of the genus Plasmodium. Five species of Plasmodium cause infection in humans, with the majority of lethal cases caused by Plasmodium falciparum. This species is responsible for more than 500 million clinical cases of malaria each year (59). In the past 2 decades, efforts to combat this disease have been met with the emergence of widespread resistance to most of the commonly used antimalarial drugs (68). The poor efficacy of current drugs and the lack of a promising vaccine have resulted in alarming increases in the rates of malaria morbidity and mortality worldwide, with the major toll felt in the developing world.P. falciparum is transmitted to humans via the bite of an infected female anopheline mosquito. In humans, the parasite undergoes one cycle of asexual multiplication in hepatocytes, followed by several cycles of infection and multiplication in red blood cells. Whereas the hepatocytic stage is asymptomatic, the erythrocytic stage is accompanied by the destruction of the host erythrocytes, resulting in anemia and, in the absence of treatment, death. Extensive efforts are presently under way to develop a vaccine, and advances in our understanding of the biology of the parasite and its metabolic and nutritional needs offer new routes for chemotherapy. In this regard, purine metabolism holds significant promise as a target for drug development.It has long been recognized that protozoan parasites, including Plasmodium spp., are unable to synthesize purine rings de novo (4). Consistent with this observation, the sequencing of protozoan genomes has failed to uncover any genes encoding enzymes involved in the biosynthesis of purine nucleosides or nucleobases (12). Protozoan parasites rely instead on salvage of purines from the host. The strategies used in acquiring purines vary significantly among parasite genera. This review will focus primarily on the purine salvage pathways present in the Plasmodium parasite. Recent reviews have examined the metabolic pathways for purine salvage in other protozoa (11,17,29).Initial studies on purine and pyrimidine synthesis in Plasmodium parasites were performed on erythrocytic stages of the rodent malaria species P. berghei (7,8,65), the macaque monkey malaria species P. knowlesi (46), and the avian malaria parasite P. lophurae (61,66 (46). Following on from these findings, Gutteridge and Trigg found that, in P. knowlesi, all radiolabeled purines were significantly incorporated into nucleic acids while none of the pyrimidines tested were (28). These early biochemical studies demonstrated that Plasmodium parasites lack the ability to metabolize exogenous pyrimidines and instead are entirely dependent on de novo synthesis. Conversely, Plasmodium parasites are entirely reliant upon the salvage of extracellular purines (4) and are capable of metabolizing a wide variety of exogenous purine nucleobases and nucleosides.The continuous culture of P. falciparum in serum-free media is dependent upon the supply of exogenous purines (1, 43), sug...

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“…The toxicity of 5-fluoroorotate was evaluated on four human cell lines (HT-1080, IMR-90, HeLa S3, and HL-60) Two lines of evidence suggested that malarial parasites were unable to utilize exogenous preformed pyrimidines. First, early studies showed that radioactive carbon dioxide was incorporated into pyrimidine units of malarial nucleic acids while uracil, uridine, thymine, thymidine, cytidine, and deoxycytidine were not (3,13,35,39,40 species of Plasmodia were shown to carry enzymes for de novo pyrimidine biosynthesis but not for the salvage of preformed pyrimidines (10-12, 17, 19, 30, 32). In contrast, mammalian cells utilize preformed pyrimidine bases and nucleosides by salvage pathways (18,24,41).…”

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Selective activity of 5-fluoroorotic acid against Plasmodium falciparum in vitro

Rathod

Khatri

Hubbert

et al. 1989

Antimicrob Agents Chemother

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Unlike mammalian cells, malarial parasites are completely dependent on de novo pyrimidine metabolism. Even though these parasites do not use external uracil or uridine, orotic acid, an intermediate of pyrimidine biosynthesis, is successfully transported into the parasite and incorporated into parasite nucleic acids. On this basis, it was hypothesized that 5-fluoroorotate, a cytotoxic derivative of orotic acid, may be a potent and selective antimalarial agent. In vitro, 5-fluoroorotate caused 50% inhibition of the growth of Plasmodium falciparum at a concentration of 6.0 nM. In contrast, 5-fluorouracil, 5-fluorouridine, and 5-fluoro 2'-deoxyuridine were much less effective against malarial parasites. Chloroquine-susceptible and chloroquineresistant clones of P. falciparum were equally susceptible to 5-fluoroorotate. The toxicity of 5-fluoroorotate was evaluated on four human cell lines (HT-1080, IMR-90, HeLa S3, and HL-60) Two lines of evidence suggested that malarial parasites were unable to utilize exogenous preformed pyrimidines. First, early studies showed that radioactive carbon dioxide was incorporated into pyrimidine units of malarial nucleic acids while uracil, uridine, thymine, thymidine, cytidine, and deoxycytidine were not (3,13,35,39,40 species of Plasmodia were shown to carry enzymes for de novo pyrimidine biosynthesis but not for the salvage of preformed pyrimidines (10-12, 17, 19, 30, 32). In contrast, mammalian cells utilize preformed pyrimidine bases and nucleosides by salvage pathways (18,24,41).Any compound with schizonticidal activity has to be transported across the three membranes that separate the host plasma from the cytoplasm of the parasite. Gutteridge and Trigg demonstrated that radioactive orotic acid, an intermediate in de novo pyrimidine biosynthesis, was effectively transported and incorporated into Plasmodium nucleic acids (13). This led us to the hypothesis that an analog of orotic acid which inhibits de novo pyrimidine metabolism would inhibit the growth of malarial parasites.To test this hypothesis, we considered 5-fluoroorotate as a model antimalarial drug. The uptake and metabolism of 5-fluoro-pyrimidines have not been studied in malarial parasites. Nevertheless, we expected the fluorinated analog to be transported into the parasite as effectively as orotic acid because the substitution of a fluorine for a proton at the 5 position represents a minimum structural alteration. In mammalian cells, 5-fluoroorotate is metabolized to toxic 5-fluoropyrimidines with the aid of orotate phosphoribosyltransferase, orotidylate decarboxylase, and other enzymes of de novo pyrimidine metabolism (7,16,31). Since malarial parasites express enzymes of de novo pyrimidine biosynthesis, we inferred that P. falciparum, too, would have the capacity to activate 5-fluoroorotate to toxic metabolites.In this study, we examine the in vitro antimalarial properties of 5-fluoroorotate against the human pathogen P. falciparum in culture. We also report the effect of this compound on the proliferation of mam...

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The Source of Purines and Pyrimidines in Plasmodium Berghei *

Cited by 69 publications

References 0 publications

METABOLISM OF BABESIA PARASITES IN VITRO. GLUCOSE AND ENERGY METABOLISM AND SURVIVAL OF BABESIA RODHAINI IN A BASAL MEDIUM WITH AND WITHOUT ADENOSINE

METABOLISM OF BABESIA PARASITES IN VITRO. GLUCOSE AND ENERGY METABOLISM AND SURVIVAL OF BABESIA RODHAINI IN A BASAL MEDIUM WITH AND WITHOUT ADENOSINE

Purine Salvage Pathways in the Intraerythrocytic Malaria Parasite Plasmodium falciparum

Selective activity of 5-fluoroorotic acid against Plasmodium falciparum in vitro

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