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Functional consequences of perturbing polyamine metabolism in the malaria parasite, Plasmodium falciparum

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Abstract

Inhibition of polyamine biosynthesis and/or the perturbation of polyamine functionality have been exploited with success against parasitic diseases such as Trypanosoma infections. However, when the classical polyamine biosynthesis inhibitor, α-difluoromethylornithine, is used against the human malaria parasite, Plasmodium falciparum, it results in only a cytostatic growth arrest. Polyamine metabolism in this parasite has unique properties not shared by any other organism. These include the bifunctional arrangement of the catalytic decarboxylases and an apparent absence of the typical polyamine interconversion pathways implying different mechanisms for the regulation of polyamine homeostasis that includes the uptake of exogenous polyamines at least in vitro. These properties make polyamine metabolism an enticing drug target in P. falciparum provided that the physiological and functional consequences of polyamine metabolism perturbation are understood. This review highlights our current understanding of the biological consequences of inhibition of the biosynthetic enzymes in the polyamine pathway in P. falciparum as revealed by several global analytical approaches. Ultimately, the evidence suggests that polyamine metabolism in P. falciparum is a validated drug target worth exploiting.

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Abbreviations

ADA:

Adenosine deaminase

AdoDATO:

S-Adenosyl-1,8-diamino-3-thiooctane

AdoHC:

S-Adenosylhomocysteine

AdoMet:

S-Adenosylmethionine

AdoMetDC:

S-Adenosylmethionine decarboxylase

AdoMetSyn:

S-Adenosylmethionine synthase

AHC:

S-Adenosyl homocysteinase

APA:

3-Aminooxy-1-aminopropane

APE:

5-Amino-1-pentene

CHA:

Cyclohexylamine

CQ:

Chloroquine

dcAdoMet:

Decarboxylated S-adenosylmethionine

DFMO:

α-Difluoromethylornithine

eIF5A:

Eukaryotic translation initiation factor 5A

EMP:

Erythrocyte plasma membrane

HC:

Homocysteine

HS:

Homospermidine

LDC:

Lysine decarboxylase

4-MCHA:

trans-1,4-Methylcyclohexylamine

MDL73811/AbeAdo:

5′-{[(Z)-4-Amino-2-butenyl]methylamino}-5′-deoxyadenosine

MDL27695:

N,N′-Bis{3-(phenylmethyl)aminolpropyl}-1,7-diaminoheptane

MetSyn:

Methionine synthase

MGBG:

Methylglyoxal bis(guanylhydrazone)

MTA:

5′-Methylthioadenosine

MTI:

5′-Methylthioinosine

MTRP:

5′-Methylthio-d-ribose-1-phosphate

OAT:

Ornithine aminotransferase

ODC:

Ornithine decarboxylase

PNP:

Uridine phosphorylase

PPM:

Parasite plasma membrane

PVM:

Parasite vacuolar membrane

SpdSyn:

Spermidine synthase

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Acknowledgments

This work was supported by the National Research Foundation of South Africa (NRF: Grant FA2004051300055, FA2006040400011 and FA2007050300003), the University of Pretoria and the Department of Science and Technology of South Africa for funding the South African Malaria Initiative of which LB and AIL are members. KC, TvB, SS and MW were recipients of prestigious bursaries from the NRF, South Africa. JN hold bursaries from the Carl and Emily Fuchs Foundation as well as the Ernst and Ethel Eriksen Trust. Any opinion, findings and conclusions or recommendations expressed in this paper are those of the author(s) and therefore the NRF does not accept any liability in regard hereto.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Natural and Agricultural Science, University of Pretoria, Pretoria, 0002, South Africa

    K. Clark, J. Niemand, S. Reeksting, S. Smit, M. Williams, A. I. Louw & L. Birkholtz

  2. CSIR Biosciences, P.O. Box 395, Pretoria, 0001, South Africa

    A. C. van Brummelen

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  1. K. Clark
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  2. J. Niemand
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  3. S. Reeksting
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  4. S. Smit
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  5. A. C. van Brummelen
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  7. A. I. Louw
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Correspondence to L. Birkholtz.

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Clark, K., Niemand, J., Reeksting, S. et al. Functional consequences of perturbing polyamine metabolism in the malaria parasite, Plasmodium falciparum . Amino Acids 38, 633–644 (2010). https://doi.org/10.1007/s00726-009-0424-7

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