Irreversible inhibition of S-adenosylmethionine decarboxylase in Plasmodium falciparum-infected erythrocytes: Growth inhibition in vitro

Wright, Paul S.; Byers, T L; Cross-Doersen, Doreen; McCann, Peter P.; Bitonti, Alan J.

doi:10.1016/0006-2952(91)90174-4

Cited by 51 publications

(45 citation statements)

References 22 publications

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“…Combination studies with APA-derived ODC inhibitors and the established AdoMetDC inhibitor MDL 73811 revealed an additive effect but no synergistic effect on P. falciparum growth (data not shown), which is in accordance with the previously obtained data for the combination of DFMO and MDL 73811 (41).…”

Section: Resultssupporting

confidence: 81%

“…Classical ODC and AdoMetDC inhibitors, like ␣-difluoromethylornithine (DFMO), methylglyoxal bis(guanylhydrazone) (MGBG), and MDL 73811, have been used in previous attempts to interfere with the polyamine synthesis in P. falciparum and other Plasmodium species (3,6,7,11,12,14,41). Sporozoite formation in the insect vector as well as the development of liver stages was sensitive to DFMO, whereas the erythrocytic stages of Plasmodium were hardly affected by these inhibitors in vivo.…”

mentioning

confidence: 99%

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3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

Gupta

Krause-Ihle

Bergmann

et al. 2005

Antimicrob Agents Chemother

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The intraerythrocytic development of Plasmodium falciparum correlates with increasing levels of the polyamines putrescine, spermidine, and spermine in the infected red blood cells; and compartmental analyses revealed that the majority is associated with the parasite. Since depletion of cellular polyamines is a promising strategy for inhibition of parasite proliferation, new inhibitors of polyamine biosynthesis were tested for their antimalarial activities. The ornithine decarboxylase (ODC) inhibitor 3-aminooxy-1-aminopropane (APA) and its derivatives CGP 52622A and CGP 54169A as well as the S-adenosylmethionine decarboxlyase (AdoMetDC) inhibitors CGP 40215A and CGP 48664A potently affected the bifunctional P. falciparum ODC-AdoMetDC, with K i values in the low nanomolar and low micromolar ranges, respectively. Furthermore, the agents were examined for their in vitro plasmodicidal activities in 48-h incubation assays. APA, CGP 52622A, CGP 54169A, and CGP 40215A were the most effective, with 50% inhibitory concentrations below 3 M. While the effects of the ODC inhibitors were completely abolished by the addition of putrescine, growth inhibition by the AdoMetDC inhibitor CGP 40215A could not be antagonized by putrescine or spermidine. Moreover, CGP 40215A did not affect the cellular polyamine levels, indicating a mechanism of action against P. falciparum independent of polyamine synthesis. In contrast, the ODC inhibitors led to decreased cellular putrescine and spermidine levels in P. falciparum, supporting the fact that they exert their antimalarial activities by inhibition of the bifunctional ODC-AdoMetDC.

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Section: Resultssupporting

confidence: 81%

mentioning

confidence: 99%

3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

Gupta

Krause-Ihle

Bergmann

et al. 2005

Antimicrob Agents Chemother

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“…Under in vitro conditions, inhibition of this enzyme by compounds such as DFMO results in growth arrest of the intra-erythrocytic P. falciparum parasite. This arrest can be overcome by the addition of exogenous polyamines (Assaraf et al, 1987b;Das Gupta et al, 2005;Wright et al, 1991), consistent with the presence in the parasite of polyamine uptake mechanism(s). Disruption of polyamine metabolism as a basis for antimalarial chemotherapy may therefore require the inhibition of both polyamine biosynthesis and the uptake of exogenous polyamines.…”

Section: Introductionmentioning

confidence: 74%

Polyamine uptake by the intraerythrocytic malaria parasite, Plasmodium falciparum

Niemand

Louw

Birkholtz

et al. 2012

International Journal for Parasitology

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Polyamines and the enzymes involved in their biosynthesis are present at high levels in rapidly proliferating cells, including cancer cells and protozoan parasites. Inhibition of polyamine biosynthesis in asexual blood-stage malaria parasites causes cytostatic arrest of parasite development under in vitro conditions, but does not cure infections in vivo. This may be due to replenishment of the parasite's intracellular polyamine pool via salvage of exogenous polyamines from the host. However the mechanism(s) of polyamine uptake by the intra-erythrocytic parasite are not well understood. In this study, the uptake of the polyamines putrescine and spermidine into Plasmodium falciparum parasites functionally isolated from their host erythrocyte were investigated using radioisotope flux techniques. Both putrescine and spermidine were taken up into isolated parasites via a temperature-dependent process that showed cross-competition between different polyamines. There was also some inhibition of polyamine uptake by basic amino acids. Inhibition of polyamine biosynthesis led to an increase in the total amount of putrescine and spermidine taken up from the extracellular medium. The uptake of putrescine and spermidine by isolated parasites was independent of extracellular Na + but increased with increasing external pH. Uptake also showed a marked dependence on the parasite's membrane potential, decreasing with membrane depolarization and increasing with membrane hyperpolarization. The data are consistent with polyamines being taken up into the parasite via an electrogenic uptake process, energized by the parasite's inwardly negative membrane potential.

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“…5'(Z)-[4-amino-2-butenyl] metylamino-5'deoxyadenosine, an irreversible inhibitor of AdoMetDC, resulted in prevention of growth of the parasite in vitro (Wright et al 1991). This inhibition could be partially reversed by coincubation of the parasites with spermidine and spermine, but not with putrescine.…”

Section: Spermidine Biosynthesis and Metabolism In Plasmodium Falciparummentioning

confidence: 81%

Spermidine metabolism in parasitic protozoa - a comparison to the situation in prokaryotes, viruses, plants and fungi

Kaiser¹,

Gottwald²,

Wiersch³

et al. 2003

FOLIA PARASIT

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Abstract. Targeting polyamines of parasitic protozoa in chemotherapy has attracted attention because polyamines might reveal novel drug targets for antiparasite therapies (Müller et al. 2001). The biological function of the triamine spermidine in parasitic protozoa has not been studied in great detail although the results obtained mainly imply three different functions, i.e., cell proliferation, cell differentiation, and biosynthesis of macromolecules. Sequence information from the malaria genome project databases and inhibitor studies provide evidence that the current status of spermidine research has to be extended since enzymes of spermidine metabolism are present in the parasite (Kaiser et al. 2001). Isolation and characterisation of these enzymes, i.e., deoxyhypusine synthase (EC 1.1.1.249) (DHS) and homospermidine synthase (EC 2.5.1.44) (HSS) might lead to valuable new targets in drug therapy. Currently research on spermidine metabolism is based on the deposition of the deoxyhypusine synthase nucleic acid sequence in GenBank while the activity of homospermidine synthase was deduced from inhibitor studies. Spermidine biosynthesis is catalyzed by spermidine synthase (EC 2.5.1.16) which transfers an aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine. Spermidine is also an important precursor in the biosynthesis of the unusual amino acid hypusine and the uncommon triamine homospermidine in eukaryotes, in particular in pyrrolizidine alkaloid-producing plants (Ober and Hartmann 2000). Hypusine is formed by a two-step enzymatic mechanism starting with the transfer of an aminobutyl moiety from spermidine to the ε-amino group of one of the lysine residues in the precursor protein of eukaryotic initiation factor eIF5A by DHS (Lee and Park 2000). The second step of hypusinylation is completed by deoxyhypusine hydroxylase (EC 1.14.9929) (Abbruzzese et al. 1985). Homospermidine formation in eukaryotes parallels deoxyhypusine formation in the way that in an NAD + -dependent reaction an aminobutyl moiety is transferred from spermidine. In the case of homospermidine synthase, however the acceptor is putrescine. Thus the triamine homospermidine consists of two symmetric aminobutyl moieties while there is one aminobutyl and one aminopropyl moiety present in spermidine. Here, we review the metabolism of the triamine spermidine with particular focus on the biosynthesis of hypusine and homospermidine in parasitic protozoa, i.e., Plasmodium, Trypanosoma and Leishmania, compared to that in prokaryotes i.e., Escherichia coli, a phytopathogenic virus and pyrrolizidine alkaloid-producing plants (Asteraceae) and fungi.

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Irreversible inhibition of S-adenosylmethionine decarboxylase in Plasmodium falciparum-infected erythrocytes: Growth inhibition in vitro

Cited by 51 publications

References 22 publications

3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

Polyamine uptake by the intraerythrocytic malaria parasite, Plasmodium falciparum

Spermidine metabolism in parasitic protozoa - a comparison to the situation in prokaryotes, viruses, plants and fungi

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