Evidence for the shikimate pathway in apicomplexan parasites

    Authors

    F. Roberts; C. W. Roberts; J. J. Johnson; D. E. Kyle; T. Krell; J. R. Coggins; G. H. Coombs; W. K. Milhous; S. Tzipori; D. J. P. Ferguson; D. Chakrabarti;R. McLeod

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    Abbreviated Journal Title

    Nature

    Keywords

    CHORISMATE SYNTHASE; PLASMODIUM-FALCIPARUM; NEUROSPORA-CRASSA; CLONING; GENES; ACID; 3-PHOSPHATE; SULFADOXINE; GLYPHOSATE; MECHANISMS; Multidisciplinary Sciences

    Abstract

    Parasites of the phylum Apicomplexa cause substantial morbidity, mortality and economic losses, and new medicines to treat them are needed urgently(1,2). The shikimate pathway is an attractive target for herbicides and antimicrobial agents because it is essential in algae, higher plants, bacteria and fungi, but absent from mammals(3,4). Here we present biochemical, genetic and chemotherapeutic evidence for the presence of enzymes of the shikimate pathway in apicomplexan parasites. In vitro growth of Toxoplasma gondii, Plasmodium falciparum (malaria) and Cryptosporidium parvum was inhibited by the herbicide glyphosate, a well-characterized inhibitor(3) of the shikimate pathway enzyme 5-enolpyruvyl shikimate 3-phosphate synthase. This effect on T. gondii and P. falciparum was reversed by treatment with p-aminobenzoate, which suggests that the shikimate pathway supplies folate precursors for their growth. Glyphosate in combination with pyrimethamine limited T. gondii infection in mice. Four shikimate pathway enzymes were detected in extracts of I: gondii and glyphosate inhibited 5-enolpyruvyl shikimate 3-phosphate synthase activity. Genes encoding chorismate synthase, the final shikimate pathway enzyme, were cloned from T. gondii and P.falciparum This discovery of a functional shikimate pathway in apicomplexan parasites provides several targets for the development of new antiparasite agents.

    Journal Title

    Nature

    Volume

    393

    Issue/Number

    6687

    Publication Date

    1-1-1998

    Document Type

    Article

    Language

    English

    First Page

    801

    Last Page

    805

    WOS Identifier

    WOS:000074433100053

    ISSN

    0028-0836

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