title: Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase: a target for anti-malarial chemotherapy.
abstract: The malarial parasite, Plasmodium vivax (Pv), causes a serious infectious disease found primarily in Asia and the Americas. For protozoan parasites, 6-oxopurine phosphoribosyltransferases (PRTases) provide the only metabolic pathway to synthesize the purine nucleoside monophosphates essential for DNA/RNA production. We have purified the recombinant Pv 6-oxopurine (PRTase) and compared its properties with the human and Pf enzymes. The Pv enzyme uses hypoxanthine and guanine with similar catalytic efficiency to the Pf enzyme but xanthine is not a substrate, hence we identify this enzyme as PvHGPRT. Mass spectrometry suggests that PvHGPRT contains bound magnesium ions that are removed by EDTA resulting in loss of activity. However, the addition of Mg(2+) restores activity. Acyclic nucleoside phosphonates (ANPs) are good inhibitors of PvHGPRT having K(i) values as low as 3 microM. These compounds can form the basis for the design of new drugs aimed at combating malaria caused by Pv.
authors.affiliation: The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, QLD, Australia.
authors.forename: Dianne T
authors.initials: DT
authors.lastname: Keough
authors.forename: Dana
authors.initials: D
authors.lastname: Hocková
authors.forename: Marcela
authors.initials: M
authors.lastname: Krecmerová
authors.forename: Michal
authors.initials: M
authors.lastname: Cesnek
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Ian M
authors.initials: IM
authors.lastname: Brereton
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Winzor
authors.forename: John
authors.initials: J
authors.lastname: de Jersey
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
mesh_terms: D003067:Coenzymes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D013058:Mass Spectrometry; D063065:Organophosphonates / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology; D010966:Plasmodium vivax / Q000201:enzymology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D003067:Coenzymes; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011994:Recombinant Proteins; D019271:Hypoxanthine; D006147:Guanine; D007041:Hypoxanthine Phosphoribosyltransferase; D008274:Magnesium