Title

Evidence for the shikimate pathway in apicomplexan parasites

Authors

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

Comments

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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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