title: Down-regulation of hypusine biosynthesis in Plasmodium by inhibition of S-adenosyl-methionine-decarboxylase.
abstract: An important issue facing global health today is the need for new, effective and affordable drugs against malaria, particularly in resource-poor countries. Moreover, the currently available antimalarials are limited by factors ranging from parasite resistance to safety, compliance, cost and the current lack of innovations in medicinal chemistry. Depletion of polyamines in the intraerythrocytic phase of P. falciparum is a promising strategy for the development of new antimalarials since intracellular levels of putrescine, spermidine and spermine are increased during cell proliferation. S-adenosyl-methionine-decarboxylase (AdoMETDC) is a key enzyme in the biosynthesis of spermidine. The AdoMETDC inhibitor CGP 48664A, known as SAM486A, inhibited the separately expressed plasmodial AdoMETDC domain with a Km( i ) of 3 microM resulting in depletion of spermidine. Spermidine is an important precursor in the biosynthesis of hypusine. This prompted us to investigate a downstream effect on hypusine biosynthesis after inhibition of AdoMETDC. Extracts from P. falciparum in vitro cultures that were treated with 10 microM SAM 486A showed suppression of eukaryotic initiation factor 5A (eIF-5A) in comparison to the untreated control in two-dimensional gel electrophoresis. Depletion of eIF-5A was also observed in Western blot analysis with crude protein extracts from the parasite after treatment with 10 microM SAM486A. A determination of the intracellular polyamine levels revealed an approximately 27% reduction of spemidine and a 75% decrease of spermine while putrescine levels increased to 36%. These data suggest that inhibition of AdoMetDc provides a novel strategy for eIF-5A suppression and the design of new antimalarials.
authors: Hochschule Bonn-Rhein-Sieg, Von Liebig Strasse 20, 53359, Rheinbach, Germany.
authors: Robert
authors: R
authors: Blavid
authors: Peter
authors: P
authors: Kusch
authors: Joachim
authors: J
authors: Hauber
authors: Ute
authors: U
authors: Eschweiler
authors: Salem Ramadan
authors: SR
authors: Sarite
authors: Sabine
authors: S
authors: Specht
authors: Susanne
authors: S
authors: Deininger
authors: Achim
authors: A
authors: Hoerauf
authors: Annette
authors: A
authors: Kaiser
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007700:Kinetics; D016778:Malaria, Falciparum / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011700:Putrescine / Q000096:biosynthesis*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D012437:Adenosylmethionine Decarboxylase; D000578:Amidines; D004791:Enzyme Inhibitors; D007189:Indans; D010448:Peptide Initiation Factors; D015800:Protozoan Proteins; D011700:Putrescine; D016601:RNA-Binding Proteins; D013095:Spermidine; D013096:Spermine; D000097574:Eukaryotic Translation Initiation Factor 5A; C082408:4-amidinoindan-1-one 2'-amidinohydrazone