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J. Biol. Chem., Vol. 277, Issue 44, 42066-42073, November 1, 2002
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From the Comparison of the malaria parasite and mammalian
protein prenyltransferases and their cellular substrates is important
for establishing this enzyme as a target for developing antimalarial agents. Nineteen heptapeptides differing only in their
carboxyl-terminal amino acid were tested as alternative substrates of
partially purified Plasmodium falciparum protein
farnesyltransferase. Only NRSCAIM and NRSCAIQ serve as substrates, with
NRSCAIM being the best. Peptidomimetics, FTI-276 and GGTI-287, inhibit
the transferase with IC50 values of 1 and 32 nM, respectively. Incubation of P. falciparum-infected erythrocytes with
[3H]farnesol labels 50- and 22-28-kDa proteins, whereas
[3H]geranylgeraniol labels only 22-28-kDa proteins. The
50-kDa protein is shown to be farnesylated, whereas the 22-28-kDa
proteins are geranylgeranylated, irrespective of the labeling prenol.
Protein labeling is inhibited more than 50% by either 5 µM FTI-277 or GGTI-298. The same concentration of
inhibitors also inhibits parasite growth from the ring stage by 50%,
decreases expression of prenylated proteins as measured with
prenyl-specific antibody, and inhibits parasite differentiation beyond
the trophozoite stage. Furthermore, differentiation specific
prenylation of P. falciparum proteins is demonstrated.
Protein labeling is detected predominantly during the trophozoite to
schizont and schizont to ring transitions. These results demonstrate
unique properties of protein prenylation in P. falciparum:
a limited specificity of the farnesyltransferase for peptide substrates
compared with mammalian enzymes, the ability to use farnesol to label
both farnesyl and geranylgeranyl moieties on proteins, differentiation
specific protein prenylation, and the ability of peptidomimetic
prenyltransferase inhibitors to block parasite differentiation.
Protein Farnesyltransferase and Protein Prenylation in
Plasmodium falciparum*
,,, and Department of Molecular Biology and
Microbiology, University of Central Florida, Orlando, Florida 32816 and the § Department of Biochemistry and Molecular Biology,
University of Florida, Gainesville, Florida 32610
*
This work was supported by National Institutes of Health
Grant R01 AI43679 (to C. M. A.).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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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