TY - JOUR
T1 - Targeting a novel Plasmodium falciparum purine recycling pathway with specific immucillins
AU - Ting, Li Min
AU - Shi, Wuxian
AU - Lewandowicz, Andrzej
AU - Singh, Vipender
AU - Mwakingwe, Agnes
AU - Birck, Matthew R.
AU - Taylor Ringia, Erika A.
AU - Bench, Graham
AU - Madrid, Dennis C.
AU - Tyler, Peter C.
AU - Evans, Gary B.
AU - Furneaux, Richard H.
AU - Schramm, Vern L.
AU - Kim, Kami
PY - 2005/3/11
Y1 - 2005/3/11
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M412693200
DO - 10.1074/jbc.M412693200
M3 - Article
C2 - 15576366
AN - SCOPUS:20144384735
SN - 0021-9258
VL - 280
SP - 9547
EP - 9554
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -