Targeting a novel Plasmodium falciparum purine recycling pathway with specific immucillins

Li Min Ting, Wuxian Shi, Andrzej Lewandowicz, Vipender Singh, Agnes Mwakingwe, Matthew R. Birck, Erika A. Taylor Ringia, Graham Bench, Dennis C. Madrid, Peter C. Tyler, Gary B. Evans, Richard H. Furneaux, Vern L. Schramm, Kami Kim

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97 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9547-9554
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number10
DOIs
StatePublished - Mar 11 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ting, L. M., Shi, W., Lewandowicz, A., Singh, V., Mwakingwe, A., Birck, M. R., Taylor Ringia, E. A., Bench, G., Madrid, D. C., Tyler, P. C., Evans, G. B., Furneaux, R. H., Schramm, V. L., & Kim, K. (2005). Targeting a novel Plasmodium falciparum purine recycling pathway with specific immucillins. Journal of Biological Chemistry, 280(10), 9547-9554. https://doi.org/10.1074/jbc.M412693200