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 (Ado-METDC) 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 lM 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 lM SAM 486A showed suppression of eukaryotic initiation factor 5A (eIF-5A) in comparison to the untreated control in twodimensional gel electrophoresis. Depletion of eIF-5A was also observed in Western blot analysis with crude protein extracts from the parasite after treatment with 10 lM 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.

Binding and inhibition of human spermidine synthase by decarboxylated S‐adenosylhomocysteine

“…[1][2][3][4][5][6][7] Spermidine is a major polyamine that serves multiple functions in growth including its role as a precursor of hypusine, which is essential for the activity of the eukaryotic initiation factor elF-5A. [8][9][10][11] Polyamines are formed in eukaryotes and in many, but not all, prokaryotes by the action of aminopropyltransferases. These comprise a class of enzymes that use decarboxylated S-adenosylmethionine (dcAdoMet) as a substrate and transfer the aminopropyl group to an amine acceptor molecule generating 5 0 -deoxy-5 0 -methylthioadenosine (MTA) as a byproduct.…”

Pharmacological potential of biogenic amine–polyamine interactions beyond neurotransmission

“…In fact, the first ODC inhibitor, difluoromethyl ornithine (DFMO), is effective as a anti-parasitic treatment, together with other polyamine analogues and this strategy has shown promise against several parasite infections, especially in combined therapies (Müller et al, 2008). Another potential lead is that P. falciparum growth in vitro was inhibited by the putrescine analogue, 1-amino-oxy-3-aminopropane (Das Gupta et al, 2005), and with inhibitors of spermidine synthesis (Blavid et al, 2010). However, P. berghei seems to be more resistant than P. falciparum to intervention with polyamine synthesis analogues or inhibitors (Wright et al, 1991).…”