Targeting enzymes involved in spermidine metabolism of parasitic protozoa—a possible new strategy for anti-parasitic treatment

Kaiser, Annette; Gottwald, A; Maier, Walter; Seitz, H. M.

doi:10.1007/s00436-003-0970-y

Cited by 27 publications

(27 citation statements)

References 53 publications

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“…Spermidine is an important substrate of DHS, the enzyme which catalyzes the first step in the biosynthesis of hypusine modification in eIF-5A. In Plasmodium eIF-5A is involved in cell proliferation (Kaiser et al 2003). A low-molecular weight drug like the AdoMetDC inhibitor SAM486A suppresses hypusine formation by spermidine depletion.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of hypusine biosynthesis in plasmodium by inhibition of S-adenosyl-methionine-decarboxylase

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of hypusine biosynthesis in plasmodium by inhibition of S-adenosyl-methionine-decarboxylase

et al. 2009

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“…Expression and purification of P. vivax eIF-5A and P. falciparum DHS protein on nickel-nitrilotriacetic acid spin columns under native conditions Escherichia coli cell cultures harboring the Plasmodium eIF-5A and dhs expression plasmids (Kaiser et al 2003 andNjuguna et al 2006) were grown in 200 ml Luria Bertani (LB) medium with the appropriate antibiotic (ampicillin 50 μg) for 15.5 h overnight at 37°C until an OD 600 of 1.5-1.6 was reached. One hour after the addition of 50 ml LB medium, cells were induced with 0.4 mM IPTG.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently cloned dhs and eIF-5A genes from the human pathogenic malaria parasites P. falciparum (Kaiser et al 2003) and Plasmodium vivax (Njuguna et al 2006). Only 48% of P. falciparum DHS amino acids are identical to the human homolog (transcript 1), while its amino acids are 44% identical to the DHS protein from P. vivax.…”

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confidence: 98%

The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria—inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase

Specht¹,

Sarite²,

Hauber

et al. 2008

Parasitol Res

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Malaria is still a major cause of death in the tropics. There is an urgent need for new anti-malarial drugs because drug-resistant plasmodia frequently occur. Over recent years, we elucidated the biosynthesis of hypusine, a novel amino acid contained in eukaryotic initiation factor 5A (eIF-5A) in Plasmodium. Hypusine biosynthesis involves catalysis of deoxyhypusine synthase (DHS) in the first step of post-translational modification. In a screen for new inhibitors of purified plasmodium DHS, CNI-1493, a novel selective pro-inflammatory cytokine inhibitor used in clinical phase II for the treatment of Crohn's disease, inhibited the enzyme of the parasite 3-fold at a concentration of 2 microM. In vitro experiments with 200 microM CNI-1493 in Plasmodium-infected erythrocytes, which lack nuclei and DHS protein, showed a parasite clearance within 2 days. This can presumably be attributed to an anti-proliferating effect because of the inhibition of DHS by the parasite. The determined IC50 of CNI-1493 was 135.79 microM after 72 h. In vivo application of this substance in Plasmodium berghei ANKA-infected C57BL/6 mice significantly reduced parasitemia after dosage of 1 mg/kg or 4 mg/kg/body weight and prevented death of mice with cerebral malaria. This effect was paralleled by a decrease in serum TNF levels of the mice. We suggest that the new mechanism of CNI-1493 is caused by a decrease in modified eIF-5A biosynthesis with a downstream effect on the TNF synthesis of the host. From the current data, we consider CNI-1493 to be a promising drug for anti-malarial therapy because of its combined action, i.e., the decrease in eIF-5A biosynthesis of the parasite and host cell TNF biosynthesis.

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“…Other protein modifications may modify specific proteins, but still be crucial to the survival of the cell. Such is the case for spermine dependent synthesis of the modified amino acid hypusine in eukaryotic translation initiation factor (eIF-5A) [63]. Studies in yeast and mammalian cells show that functional eIF-5A is essential to cell proliferation, without it cells arrest at the G1-S boundary of the cell cycle [63].…”

Section: Protein Modificationmentioning

confidence: 99%

Drug Targets for Plasmodium falciparum: A Post-Genomic Review/Survey

Yeh

Altman²

2006

MRMC

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Over 300 million cases of malaria each year cause significant morbidity and mortality. Growing drug-resistance among the Plasmodia that cause malaria motivates the development of additional anti-malarial drugs. This review summarizes the current state of knowledge about potential drug targets for malaria. The recently sequenced malaria genome data clarifies parasite metabolic pathways, and more metabolic targets have been identified.

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Targeting enzymes involved in spermidine metabolism of parasitic protozoa—a possible new strategy for anti-parasitic treatment

Cited by 27 publications

References 53 publications

Down-regulation of hypusine biosynthesis in plasmodium by inhibition of S-adenosyl-methionine-decarboxylase

Down-regulation of hypusine biosynthesis in plasmodium by inhibition of S-adenosyl-methionine-decarboxylase

The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria—inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase

Drug Targets for Plasmodium falciparum: A Post-Genomic Review/Survey

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