Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase: a target for anti-malarial chemotherapy.
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.
Keough
Dianne T
DT
The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, QLD, Australia.
Hocková
Dana
D
Krecmerová
Marcela
M
Cesnek
Michal
M
Holý
Antonín
A
Naesens
Lieve
L
Brereton
Ian M
IM
Winzor
Donald J
DJ
de Jersey
John
J
Guddat
Luke W
LW
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
D003067:Coenzymes; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011994:Recombinant Proteins; D019271:Hypoxanthine; D006147:Guanine; D007041:Hypoxanthine Phosphoribosyltransferase; D008274:Magnesium