Protein prenyl transferase activities of Plasmodium falciparum

    Authors

    D. Chakrabarti; T. Azam; C. DelVecchio; L. B. Qiu; Y. Park;C. M. Allen

    Comments

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    Abbreviated Journal Title

    Mol. Biochem. Parasitol.

    Keywords

    protein prenylation; Plasmodium falciparum; farnesyl transferase; geranylgeranyl transferase; schizont; trophozoite; HUMAN MALARIA PARASITES; GTP-BINDING PROTEINS; SCHISTOSOMA-MANSONI; TRYPANOSOMA-BRUCEI; RAS FARNESYLATION; FARNESYLTRANSFERASE; INHIBITORS; GERANYLGERANYLTRANSFERASE; ISOPRENYLATION; MEVALONATE; Biochemistry & Molecular Biology; Parasitology

    Abstract

    Prenylated proteins have been shown to function in important cellular regulatory processes including signal transduction. The enzymes involved in protein prenylation, farnesyl transferase and geranylgeranyl transferase, have been recent targets for development of cancer chemotherapeutics, We have initiated a systematic study of protein prenyl transferases of the malaria parasite, Plasmodium falciparum, to determine whether these enzymes can be developed as targets for antimalarial chemotherapy. We report here the identification of protein farnesyl transferase and protein geranylgeranyl transferase-I in the malaria parasite, P. falciparum. The farnesyl transferase has been partially purified from the cytosolic fraction through ammonium sulfate precipitation and Mono-Q chromatography. Farnesyl and geranylgeranyl transferase-I activities are present at all stages of P. falciparum intraerythrocytic development with maximum specific activity in the ring stage. Geranylgeranyl transferase-I specific activity is two times that of farnesyl transferase in the ring stage. Peptidomimetics and prenyl analogues of protein farnesyl transferase substrates were tested as in vitro inhibitors of partially purified P. falciparum prenyl transferase and of malaria parasite growth. The peptidomimetics were significantly more potent inhibitors than lipid substrate analogues of both the activity of Mono-Q purified enzyme and parasite growth in intraerythrocytic cultures. Exposure of the parasite to the peptidomimetic L-745,631 also showed significant inhibition of morphological development beyond the trophozoite stage. These studies suggest the potential of designing or identifying differential inhibitors of P. falciparum and mammalian prenyl transferases as an approach to novel malaria therapy. (C) 1998 Elsevier Science B.V. All rights reserved.

    Journal Title

    Molecular and Biochemical Parasitology

    Volume

    94

    Issue/Number

    2

    Publication Date

    1-1-1998

    Document Type

    Article

    Language

    English

    First Page

    175

    Last Page

    184

    WOS Identifier

    WOS:000075534400002

    ISSN

    0166-6851

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