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Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

Journal Article · · Journal of Biological Chemistry
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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 the polyamine pathway 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 previously been described. 5'-methylthio-Immucillin-H, a transition state analogue inhibitor that is selective for malarial over human purine nucleoside phosphorylase, kills P. falciparum in culture. Immucillins are currently in clinical trials for other indications and may have application as antimalarials.
Research Organization:
Lawrence Livermore National Lab., Livermore, CA (US)
Sponsoring Organization:
US Department of Energy (US)
DOE Contract Number:
W-7405-ENG-48
OSTI ID:
15015904
Report Number(s):
UCRL-JRNL-204238
Journal Information:
Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Vol. 280; ISSN JBCHA3; ISSN 0021-9258
Country of Publication:
United States
Language:
English

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Related Subjects

43 PARTICLE ACCELERATORS
59 BASIC BIOLOGICAL SCIENCES
ACCELERATORS
ADENOSINE
CLINICAL TRIALS
ENZYMES
HYPOXANTHINE
INOSINE
MALARIA
MASS SPECTROSCOPY
NUCLEIC ACIDS
NUCLEOSIDES
PHOSPHOTRANSFERASES
PLASMODIUM
PRECURSOR
PURINES
RECYCLING