The Plasmodium falciparum Translationally Controlled Tumor Protein Homolog and Its Reaction with the Antimalarial Drug Artemisinin*
- Jamaree Bhisutthibhan‡,
- Xing-Qing Pan‡§,
- Paul A. Hossler‡,
- Daniel J. Walker‡,
- Charles A. Yowell¶,
- Jane Carlton¶,
- John B. Dame¶ and
- Steven R. Meshnick‡‖
- From the ‡Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2029 and the ¶Department of Infectious Diseases, College of Veterinary Medicine, University of Florida, Gainesville, Florida 32610
Abstract
Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of ∼18 μm. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.
Footnotes
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↵* This work was supported by National Institutes of Heath Grant AI-26848 and a grant from the Burroughs Wellcome Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Current address: Dept. of Cell and Tumor Biology, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010-3000.
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↵‖ To whom correspondence should be addressed: Dept. of Epidemiology, University of Michigan School of Public Health, Ann Arbor MI 48109-2029. Tel.: 734-647-2406; Fax: 734-764-3192; E-mail:meshnick{at}umich.edu.
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↵1 The abbreviations used are: TCTP, translationally controlled tumor protein; IA, iodoacetamide; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; CAPS, 3-(cyclohexylamino)propanesulfonic acid; Tricine,N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine .
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- Received December 16, 1997.
- Revision received April 2, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
