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Artemisinins target the SERCA of Plasmodium falciparum

Nature, 2003-08, Vol.424 (6951), p.957-961 [Peer Reviewed Journal]

COPYRIGHT 2003 Nature Publishing Group ;Copyright Macmillan Journals Ltd. Aug 21, 2003 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature01813 ;PMID: 12931192 ;CODEN: NATUAS

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Title:
Artemisinins target the SERCA of Plasmodium falciparum
Author: Krishna, S ; Eckstein-Ludwig, U ; Webb, R. J ; van Goethem, I. D. A ; East, J. M ; Lee, A. G ; Kimura, M ; O'Neill, P. M ; Bray, P. G ; Ward, S. A
Subjects: Animals ; Artemisia annua ; Artemisinins - antagonists & inhibitors ; Artemisinins - pharmacology ; ATP6 protein ; Calcium-Transporting ATPases - antagonists & inhibitors ; Calcium-Transporting ATPases - genetics ; Calcium-Transporting ATPases - metabolism ; Culicidae ; Deferoxamine - pharmacology ; Freshwater ; Glucose - metabolism ; Iron ; Iron - metabolism ; Iron Chelating Agents - pharmacology ; Oocytes ; Plasma ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - enzymology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; Thapsigargin - pharmacology ; Xenopus laevis
Is Part Of: Nature, 2003-08, Vol.424 (6951), p.957-961
Description: Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/nature01813
PMID: 12931192
CODEN: NATUAS
Source: ProQuest One Psychology
AUTh Library subscriptions: ProQuest Central
MEDLINE
Alma/SFX Local Collection

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Artemisinins target the SERCA of Plasmodium falciparum

COPYRIGHT 2003 Nature Publishing Group ;Copyright Macmillan Journals Ltd. Aug 21, 2003 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature01813 ;PMID: 12931192 ;CODEN: NATUAS

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