Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum

Reyes, Philip; Rathod, Pradipsinh K.; Sanchez, Donald J.; Mrema, J. E. K.; Rieckmann, Karl H.; Heidrich, Hans-G.

doi:10.1016/0166-6851(82)90035-4

Cited by 204 publications

(154 citation statements)

References 32 publications

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“…PfADA Converts MTA to MTI-An unusual feature of P. falciparum is the expression of PfADA, PfPNP, and hypoxanthine-guanine-xanthine phosphoribosyltransferase at 4 -700 times the specific activity found in human erythrocytes, far exceeding the rate of purine salvage in this purine auxotroph (14). P. falciparum grows in ADA-or PNP-deficient erythro-cytes, establishing the competence of parasite-expressed enzymes for purine salvage (18,19).…”

Section: Resultsmentioning

confidence: 99%

“…The C. parvum AK was recently proven to be functional (13). Earlier biochemical reports of AK and APRTase activity in extracts of Plasmodium isolated from human erythrocytes gave activities not significantly greater than in the erythrocytes (14).…”

Section: Methodsmentioning

confidence: 99%

“…In a second AMS experiment, synchronized P. falciparum cultures were incubated in triplicate for 12 h in hypoxanthine-free media and labeled with 100 fmol of the [8][9][10][11][12][13][14] C]purine for 12 h. Labeled cells were washed three times with cold PBS, and nucleic acids were precipitated and washed with 3% cold perchloric acid. Tributyrin was added as carbon carrier to decrease addition of background 14 C. In the first experiment, parasites were mostly trophozoites when label was added, whereas in the second experiment, parasites were late rings/early trophozoites.…”

Section: P Falciparum Culture and Immucillin Kill Curves-humanmentioning

confidence: 99%

“…After labeling for 48 h, cells were washed three times with unlabeled fresh medium and precipitated, and pellets were rinsed three times with 6% trichloroacetic acid, extracted with acetone, and dried. Three mg of sucrose was added as carbon carrier, and samples were converted to graphite and analyzed for the 14 C/ 12 C ratio by AMS at the Lawrence Livermore National Laboratory AMS facility (17).…”

Section: P Falciparum Culture and Immucillin Kill Curves-humanmentioning

confidence: 99%

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Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

Ting¹,

Shi

Lewandowicz

et al. 2005

Journal of Biological Chemistry

111

182

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Plasmodium falciparum is unable to synthesize purine bases and relies upon purine salvage and purine recycling to meet its purine needs. We report that purines formed as products of polyamine synthesis are recycled in a novel pathway in which 5 -methylthioinosine is generated by adenosine deaminase. The action of P. falciparum purine nucleoside phosphorylase is a convergent step of purine salvage, converting both 5 -methylthioinosine and inosine to hypoxanthine. We used accelerator mass spectrometry to verify that 5 -methylthioinosine is an active nucleic acid precursor in P. falciparum. Prior studies have shown that inhibitors of purine salvage enzymes kill malaria, but potent malaria-specific inhibitors of these enzymes have not been described previously. 5 -Methylthio-immucillin-H, a transition state analogue inhibitor that is selective for malarial relative to human purine nucleoside phosphorylase, kills P. falciparum in culture. Immucillins are currently in clinical trials for other indications and may also have application as anti-malarials.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: P Falciparum Culture and Immucillin Kill Curves-humanmentioning

confidence: 99%

Section: P Falciparum Culture and Immucillin Kill Curves-humanmentioning

confidence: 99%

See 2 more Smart Citations

Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

Ting¹,

Shi

Lewandowicz

et al. 2005

Journal of Biological Chemistry

111

182

View full text Add to dashboard Cite

show abstract

“…However, P. falciparum lacks de novo purine synthesis (purine auxotroph), and starvation of purines is known to cause purine-less death in cultured cells (Reyes et al 1982, Kicska et al 2002a). Enzymes of the purine salvage pathway were detected in P. falciparum including purine nucleoside phosphorylase (PNP), and thus the parasite must salvage purine bases from the mammalian host to survive.…”

Section: Purine Salvage Pathwaymentioning

confidence: 99%

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

Basso

Silva

Fett-Neto

et al. 2005

Mem. Inst. Oswaldo Cruz

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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum

Cited by 204 publications

References 32 publications

Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

Antimalarials

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