title: Targeting a novel Plasmodium falciparum purine recycling pathway with specific immucillins.
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.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Ting
authors.forename: Wuxian
authors.initials: W
authors.lastname: Shi
authors.forename: Andrzej
authors.initials: A
authors.lastname: Lewandowicz
authors.forename: Vipender
authors.initials: V
authors.lastname: Singh
authors.forename: Agnes
authors.initials: A
authors.lastname: Mwakingwe
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Birck
authors.forename: Erika A Taylor
authors.initials: EA
authors.lastname: Ringia
authors.forename: Graham
authors.initials: G
authors.lastname: Bench
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Madrid
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.forename: Richard H
authors.initials: RH
authors.lastname: Furneaux
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.forename: Kami
authors.initials: K
authors.lastname: Kim
mesh_terms: 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
chemical_list: D011687:Purines; D019271:Hypoxanthine; D008778:Methylthioinosine; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D000243:Adenosine Deaminase; D000225:Adenine