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Evidence for the shikimate pathway in apicomplexan parasites

Nature volume 393, pages 801–805 (1998)Cite this article

An Erratum to this article was published on 17 September 1998

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.

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Figure 1: Functional and enzymatic evidence for the shikimate pathway in T.gondii
Figure 2: Comparison of deduced amino-acid sequences of T. gondii, P. falciparum and other organisms' chorismate synthases.
Figure 3: Evidence for the shikimate pathway in P. falciparum and C. parvum.

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Acknowledgements

We thank L. Mets for information about plants; D. Sibley and the Toxoplasma EST Project at Washington University for the putative chorismate synthase EST; M. Gottlieb, J. Boothroyd, K. Kim, L. Weiss, A. Lapthorn, A. Martin, M. Rust and U. Gross for discussions; and V. Aitchison and E. Holfels for assistance in preparation of this manuscript. F.R. was a recipient of a Royal Pathological Society of Great Britain and Northern Ireland Travelling Fellowship, C.W.R. was a Fulbright Scholar, and a Michael Reese Physicians' Research and Education Foundation Postdoctoral Fellow and Visiting Scholar and is a Glaxo Jack Lecturer. R.M. is the Jules and Doris Stein Research to Prevent Blindness Professor at The University of Chicago. This work was supported by the NIH NIAID TMP program, the Toxoplasmosis Research Institute, the Research to Prevent Blindness Foundation, an NIH contract from NIH NIAID (the AIDS Opportunistic Infection Drug Discovery), and the WHO-NIH-WRAIR Drug Development Programs, The Wellcome Trust and the European Union.

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Author notes

  1. Craig W. Roberts

    Present address: University of Strathclyde, Glasgow, UK

  2. Fiona Roberts

    Present address: University of Glasgow, Glasgow, UK

  3. Fiona Roberts, Craig W. Roberts and David J. P. Ferguson: These authors contributed equally to this work.

Authors and Affiliations

  1. Michael Reese Hospital and Medical Center, Chicago, and The University of Chicago, Chicago, 60616, Illinois, USA

    Fiona Roberts, Craig W. Roberts, Jennifer J. Johnson & Rima McLeod

  2. Department of Immunology, University of Strathclyde, Glasgow, G4 0NR, UK

    Craig W. Roberts

  3. Walter Reed Army Institute of Research, Washington, 20307-5100, DC, USA

    Dennis E. Kyle & Wilbur K. Milhous

  4. Institute of Biomedical & Life Sciences, University of Glasgow, Glasgow, G12 812 8QQ, UK

    Tino Krell, John R. Coggins & Graham H. Coombs

  5. Tufts University School of Veterinary Medicine, Boston, 01536, Massachusetts, USA

    Saul Tzipori

  6. John Radcliffe Hospital, Oxford University, OX3 9DU, Oxford, UK

    David J. P. Ferguson

  7. University of Central Florida, Orlando, 32816-2360, Florida, USA

    Debopam Chakrabarti

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Correspondence to Rima McLeod.

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Roberts, F., Roberts, C., Johnson, J. et al. Evidence for the shikimate pathway in apicomplexan parasites. Nature 393, 801–805 (1998). https://doi.org/10.1038/31723

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