Assessing the polyamine metabolism of Plasmodium falciparum as chemotherapeutic target.
More than 30 years ago the potent ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) was designed as new anticancer drug. Its efficacy was not as expected since the polyamine metabolism in mammalian cells seemed to be far more complex. However when DFMO was applied to African trypanosomes its effect on this protozoan parasite was highly convincing. Thenceforward many researchers tested DFMO and also other polyamine synthesis inhibitors against different parasites among them the causative agent of malaria Plasmodium. This review recapitulates the different attempts to interfere chemically with the plasmodial polyamine metabolism, the impact on the disease as well as its biochemical and molecular background. It will show that this fast proliferating organism depends for growth on high amounts of polyamines and that Plasmodium has its own and unique polyamine synthesis, differing highly from the mammalian one mainly in the arrangement of the key enzymes, S-adenosylmethionine decarboxylase and ornithine decarboxylase (AdoMetDC/ODC), on a bifunctional protein.
Müller
Ingrid B
IB
Bernhard Nocht Institute for Tropical Medicine, Department of Biochemistry, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany. ibmueller@bni-hamburg.de
Das Gupta
Robin
R
Lüersen
Kai
K
Wrenger
Carsten
C
Walter
Rolf D
RD
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D008288:Malaria / Q000469:parasitology; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011436:Spermidine Synthase / Q000378:metabolism
D000962:Antimalarials; D011073:Polyamines; D011436:Spermidine Synthase; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D000518:Eflornithine