Evidence for the shikimate pathway in apicomplexan parasites

Fiona Roberts, Craig W. Roberts, Jennifer J. Johnson, Dennis E. Kyle, Tino Krell, John R. Coggins, Graham H. Coombs, Wilbur K. Milhous, Saul Tzipori, David J. P. Ferguson, Debopam Chakrabarti and Rima McLeod ()
Additional contact information
Fiona Roberts: Michael Reese Hospital and Medical Center, Chicago, and The University of Chicago
Craig W. Roberts: Michael Reese Hospital and Medical Center, Chicago, and The University of Chicago
Jennifer J. Johnson: Michael Reese Hospital and Medical Center, Chicago, and The University of Chicago
Dennis E. Kyle: Walter Reed Army Institute of Research
Tino Krell: Institute of Biomedical & Life Sciences, University of Glasgow
John R. Coggins: Institute of Biomedical & Life Sciences, University of Glasgow
Graham H. Coombs: Institute of Biomedical & Life Sciences, University of Glasgow
Wilbur K. Milhous: Walter Reed Army Institute of Research
Saul Tzipori: Tufts University School of Veterinary Medicine
David J. P. Ferguson: John Radcliffe Hospital, Oxford University
Debopam Chakrabarti: University of Central Florida
Rima McLeod: Michael Reese Hospital and Medical Center, Chicago, and The University of Chicago

Nature, 1998, vol. 393, issue 6687, 801-805

Abstract: Abstract Parasites of the phylum Apicomplexa cause substantial morbidity, mortality and economic losses, and new medicines to treat them are needed urgently1,2. 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 mammals3,4. 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 inhibitor3 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 T. 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.

Date: 1998
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DOI: 10.1038/31723

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