Polyamine levels and the activity of their biosynthetic enzymes in human erythrocytes infected with the malarial parasite, <i>Plasmodium falciparum</i>

Assaraf, Yehuda G.; Golenser, Jacob; Spira, Dan T.; Bachrach, Uriel

doi:10.1042/bj2220815

Cited by 73 publications

(51 citation statements)

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“…Polyamine concentrations are strictly regulated on transcriptional, translational and post-translational levels as well as by uptake and efflux processes [1]. Erythrocytes infected by Plasmodium falciparum (the causative agent of fatal malaria) contain high levels of polyamines during stages of rapid growth [6,7]. In Plasmodium spp, polyamine biosynthesis is uniquely characterised by the bifunctional arrangement of the ratelimiting decarboxylases, S-adenosylmethionine decarboxylase (PfAdoMetDC) and ornithine decarboxylase (PfODC) in a single protein, PfAdoMetDC/ODC [8].…”

Section: Introductionmentioning

confidence: 99%

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Williams

Sprenger

Human

et al. 2011

Molecular and Biochemical Parasitology

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Plasmodium falciparum like other organisms is dependent on polyamines for proliferation.Polyamine biosynthesis in these parasites is regulated by a unique bifunctional Sadenosylmethionine decarboxylase/ornithine decarboxylase (PfAdoMetDC/ODC). Only limited biochemical and structural information is available on the bifunctional enzyme due to the low levels and impurity of an instable recombinantly expressed protein from the native gene. Here we describe the high level expression of stable monofunctional PfAdoMetDC from a codon-harmonised construct, which permitted its biochemical characterisation indicating similar catalytic properties to AdoMetDCs of orthologous parasites. In the absence of structural data, far-UV CD showed that at least on secondary structure level, PfAdoMetDC corresponds well to that of the human protein. The kinetic properties of the monofunctional enzyme were also found to be different from that of PfAdoMetDC/ODC as mainly evidenced by an increased K m . We deduced that complex formation of PfAdoMetDC and PfODC could enable coordinated modulation of the decarboxylase activities since there is a convergence of their k cat and lowering of their K m . Such coordination results in the aligned production of decarboxylated AdoMet and putrescine for the subsequent synthesis of spermidine. Furthermore, based on the results obtained in this study we propose a new AdoMetDC subclass for plasmodial AdoMetDCs.

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Section: Introductionmentioning

confidence: 99%

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Williams

Sprenger

Human

et al. 2011

Molecular and Biochemical Parasitology

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“…Assaraf et al (1984) showed that polyamine levels increased in parasite-infected erythrocytes. The authors determined a 95-fold increase in putrescine and a 51-fold increase in spermidine in trophozoite and schizont enriched fractions.…”

Section: Spermidine Biosynthesis and Metabolism In Plasmodium Falciparummentioning

confidence: 99%

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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“…The asexual intraerythrocytic form of the human malaria parasite, Plasmodium falciparum, has a high internal concentration of polyamines (Assaraf et al, 1984;Teng et al, 2009). The biosynthesis of polyamines by this parasite has some unusual features (Müller et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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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Polyamine levels and the activity of their biosynthetic enzymes in human erythrocytes infected with the malarial parasite, Plasmodium falciparum

Cited by 73 publications

References 10 publications

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum

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

Polyamine uptake by the intraerythrocytic malaria parasite, Plasmodium falciparum

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