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

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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 μM 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 μM 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 μM 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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Abbreviations

AdoMetDC:

S-adenosylmethionine decarboxylase

EIF-5A:

Eukaryotic initiation factor 5A

ODC:

Ornithine decarboxylase

DHS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

SAM486A:

4-amidinoindan-1-one-2′-amidinohydrazone

kDa:

Kilodalton

p.i.:

Post infection

RBC:

Red blood cells

Put:

Putescine

Spd:

Spermidine

Spm:

Spermine

References

  • Andrus L, Szabo P, Grady RW, Hanauske AR, Huima-Byron T, Slowinska B, Zagulska S, Hanauske-Abel HM (1998) Antiretroviral effects of deoxyhypusyl hydroxylase inhibitors: a hypusine-dependent host cell mechanism for relication of human immunodeficiency virus type 1 (HIV-1). Biochem Pharmacol 55:1807–1818

    Article  CAS  PubMed  Google Scholar 

  • Brun R, Buhler Y, Sandmeier U, Kaminsky R, Bacchi CJ, Rattendi D, Lane S, Croft SL, Snowdon D, Yardley V, Caravatti G, Frei J, Stanek J, Mett J (1996) In vitro trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors. Antimicrob Agents Chemother 40:1442–1447

    CAS  PubMed  Google Scholar 

  • Das Gupta R, Krause-Ihle T, Bergmann B, Müller IB, Khomutov AR, Müller S, Walter RD, Lüersen K (2005) 3-Aminooxy-1-aminopropane and derivatives have an antiproliferative effect on cultured Plasmodium falciparum by decreasing intracellular polyamine concentrations. Antimicrob Agents Chemother 49:2857–2864

    Article  CAS  PubMed  Google Scholar 

  • Gregio AP, Cano VP, Avaca JS, Valentini SR, Zanelli CF (2009) EIF5A has a function in the elongation step of translation in yeast. Biochem Biophys Res Commun 380:785–790

    Article  CAS  PubMed  Google Scholar 

  • Haider N, Eschbach ML, Dias Sde S, Gilberger TW, Walter RD, Lüersen K (2005) The spermidine synthase of the malaria parasite Plasmodium falciparum: molecular and biochemical analysis of the polyamine synthesis enzyme. Mol Biochem Parasitol 142:224–236

    Article  CAS  PubMed  Google Scholar 

  • Hart RA, Billaud JN, Choi SJ, Phillips TR (2002) Effects of 1, 8-diaminooctane on the FIV Rev regulatory system. Virology 304:97–104

    Article  CAS  PubMed  Google Scholar 

  • Hauber I, Bevec D, Heukeshoven J, Krätzer F, Horn F, Choidas A, Harrer T, Hauber J (2005) Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J Clin Investig 115:76–85

    CAS  PubMed  Google Scholar 

  • Kaiser A, Gottwald A, Wiersch C, Lindenthal B, Maier W, Seitz HM (2001) Effect of drugs inhibiting spermidine biosynthesis and metabolism on the in vitro development of Plasmodium falciparum. Parasitol Res 87:963–972

    CAS  PubMed  Google Scholar 

  • Kaiser A, Gottwald A, Maier W, Seitz HM (2003) Targeting enzymes involved in spermidine metabolism of parasitic protozoa-a possible new strategy for antiparasitic treatment. Parasitol Res 91:508–516

    Article  CAS  PubMed  Google Scholar 

  • Klier H, Csonga R, Joäo HC, Eckerskorn C, Auer M, Lottspeich F, Eder J (1995) Isolation and structural characterization of different isoforms of the hypusine-containing protein eIF-5A from Hela cells. Biochem 34:14693–14702

    Article  CAS  Google Scholar 

  • Liao DI, Wolff EC, Park MH, Davies DR (1998) Crystal structure of the NAD complex of the human deoxyhypusine synthase: an enzyme with a ball and chain mechanism for blocking the active site. Structure 6:23–32

    Article  CAS  PubMed  Google Scholar 

  • Müller SA, Da’dara K, Lüersen C, Wrenger R, Das Gupta R, Madhubala R, Walter RD (2000) In the human malaria parasite Plasmodium falciparum, polyamines are synthesized by a bifunctional ornithine decarboxylase, S-adenosylmethionine decarboxylase. J Biol Chem 275:8097–8102

    Article  PubMed  Google Scholar 

  • Müller S, Coombs GH, Walter RD (2001) Targeting polyamines of parasitic protozoa in chemotherapy. Trends Parasitol 17:242–249

    Article  PubMed  Google Scholar 

  • Nishimura K, Murozumi K, Shirahata A, Park MH, Kashiwagi K, Igarashi K (2005) Independent roles of eIF5A and polyamines in cell proliferation. Biochem J 385:779–785

    Article  CAS  PubMed  Google Scholar 

  • Park MH (2006) The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF5A). J Biochem 139:161–169

    Article  CAS  PubMed  Google Scholar 

  • Park JH, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH (2006) Molecular cloning, expression and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci USA 103:51–56

    Article  CAS  PubMed  Google Scholar 

  • Pless M, Belhadj K, Menssen HD, Kern W, Coiffier B, Wolf J, Herrmann R, Thiel E, Bootle D, Sklenar I, Muller C, Choi L, Porter C, Capdeville R (2004) Clinical efficacy, tolerability, and safety of SAM486A, a novel polyamine biosynthesis inhibitor, in patients with relapsed or refractory non-Hodgkin’s lymphoma: results from a phase II multicenter study. Clin Cancer Res 10:1299–1305

    Article  CAS  PubMed  Google Scholar 

  • Ramya TNC, Surolia N, Surolia A (2006) Polyamine synthesis and salvage pathways in the malaria parasite Plasmodium falciparum. Biochem Biophys Res Commun 348:579–584

    Article  CAS  PubMed  Google Scholar 

  • Redmond JW, Tseng A (1978) High-pressure liquid chromatographic determination of putrescine, cadaverine, spermidine and spermine. J Chomatogr 170:479–481

    Article  Google Scholar 

  • Regenass U, Caravatti G, Mett H, Stanek J, Schneider P, Müller M, Matter A, Vertino P, Porter CW (1992) New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity. Cancer Res 52:4712–4718

    CAS  PubMed  Google Scholar 

  • Regenass U, Mett H, Stanek J, Mueller M, Kramer D, Porter CW (1994) CGP 48664, a new S-adenosylmethionine decarboxylase inhibitor with broad spectrum antiproliferative and antitumor activity. Cancer Res 54:3210–3217

    CAS  PubMed  Google Scholar 

  • Schäfer B, Hauber I, Bunk A, Heukeshoven J, Düsedau A, Bevec D, Hauber J (2006) Inhibition of multidrug-resistant HIV-1 by interference with cellular S-adenosylmethionine decarboxylase activity. J Infect Dis 15:740–750

    Article  Google Scholar 

  • Seiler N (2003) Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors. Curr Drug Targets 4:537–564

    Article  CAS  PubMed  Google Scholar 

  • Specht S, Sarite SR, Hauber I, Hauber J, Görbig UF, Meier C, Bevec D, Hoerauf A, Kaiser A (2008) The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase. Parasitol Res 102:1177–1184

    Article  PubMed  Google Scholar 

  • Wessel D, Flügge UI (1983) A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem 138:141–143

    Article  Google Scholar 

  • Wolff EC, Kang KR, Kim YS, Park MH (2007) Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification. Amino Acids 33:341–350

    Article  CAS  PubMed  Google Scholar 

  • Wright PS, Byers TL, Cross-Doersen DE, McCann PP, Bitonti AJ (1991) Irreversible inhibition of S-adenosylmethionine decarboxylase in Plasmodium falciparum-infected erythrocytes: growth inhibition in vitro. Biochem Pharmacol 41:1713–1718

    Article  CAS  PubMed  Google Scholar 

  • Zanelli CF, Valentini SR (2007) Is there a role for eIF5A in translation? Amino Acids 33:351–358

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The compound SAM486A was kindly provided by Novartis Pharma AG Basel. This work was supported in part by grants from the German Research Foundation to A. H. and J. H.

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Authors and Affiliations

  1. Hochschule Bonn-Rhein-Sieg, Von Liebig Strasse 20, 53359, Rheinbach, Germany

    Robert Blavid, Peter Kusch, Ute Eschweiler & Annette Kaiser

  2. Heinrich-Pette-Institut, Martinistrasse 52, 20251, Hamburg, Germany

    Joachim Hauber

  3. Immunologie und Parasitologie, Institut für Mikrobiologie, 53105, Bonn, Germany

    Salem Ramadan Sarite, Sabine Specht, Susanne Deininger, Achim Hoerauf & Annette Kaiser

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  1. Robert Blavid
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  2. Peter Kusch
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  3. Joachim Hauber
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  4. Ute Eschweiler
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  5. Salem Ramadan Sarite
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  8. Achim Hoerauf
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  9. Annette Kaiser
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Correspondence to Annette Kaiser.

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Blavid, R., Kusch, P., Hauber, J. et al. Down-regulation of hypusine biosynthesis in plasmodium by inhibition of S-adenosyl-methionine-decarboxylase. Amino Acids 38, 461–469 (2010). https://doi.org/10.1007/s00726-009-0405-x

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  • DOI: https://doi.org/10.1007/s00726-009-0405-x

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