Targeting a novel Plasmodium falciparum purine recycling pathway with specific immucillins.
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.
Ting
Li-Min
LM
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Shi
Wuxian
W
Lewandowicz
Andrzej
A
Singh
Vipender
V
Mwakingwe
Agnes
A
Birck
Matthew R
MR
Ringia
Erika A Taylor
EA
Bench
Graham
G
Madrid
Dennis C
DC
Tyler
Peter C
PC
Evans
Gary B
GB
Furneaux
Richard H
RH
Schramm
Vern L
VL
Kim
Kami
K
D000225:Adenine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007288:Inosine / Q000378:metabolism; D008778:Methylthioinosine / Q000378:metabolism; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000502:physiology*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D011687:Purines; D019271:Hypoxanthine; D008778:Methylthioinosine; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D000243:Adenosine Deaminase; D000225:Adenine