Evidence for the shikimate pathway in apicomplexan parasites

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 Ferguson, D Chakrabarti, R McLeod

Research output: Contribution to journalArticle

400 Citations (Scopus)

Abstract

Parasites of the phylum Apicomplexa cause substantial morbidity, mortality and economic losses, and new medicines to treat them are needed urgently. 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. 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 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.
LanguageEnglish
Pages801-805
Number of pages5
JournalNature
Volume393
Issue number6687
DOIs
Publication statusPublished - 25 Jun 1998

Fingerprint

glyphosate
Toxoplasma
Parasites
chorismate synthase
Herbicides
Enzymes
Plasmodium falciparum
para-Aminobenzoates
Apicomplexa
Cryptosporidium parvum
Pyrimethamine
Falciparum Malaria
Toxoplasmosis
Growth
Anti-Infective Agents
Folic Acid
Molecular Biology
Mammals
Fungi
Economics

Keywords

  • 3-phosphoshikimate 1-carboxyvinyltransferase
  • alkyl and aryl transferases
  • amino acid sequence
  • animals
  • antiprotozoal agents
  • cryptosporidium parvum
  • enzyme inhibitors
  • glycine
  • herbicides
  • molecular sequence data
  • phosphorus-oxygen lyases
  • plasmodium falciparum
  • sequence homology, amino acid
  • shikimic acid
  • toxoplasma

Cite this

Roberts, F., Roberts, C. W., Johnson, J. J., Kyle, D. E., Krell, T., Coggins, J. R., ... McLeod, R. (1998). Evidence for the shikimate pathway in apicomplexan parasites. Nature, 393(6687), 801-805. https://doi.org/10.1038/31723
Roberts, F ; Roberts, C W ; Johnson, J J ; Kyle, D E ; Krell, T ; Coggins, J R ; Coombs, G H ; Milhous, W K ; Tzipori, S ; Ferguson, D J ; Chakrabarti, D ; McLeod, R. / Evidence for the shikimate pathway in apicomplexan parasites. In: Nature. 1998 ; Vol. 393, No. 6687. pp. 801-805.
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Roberts, F, Roberts, CW, Johnson, JJ, Kyle, DE, Krell, T, Coggins, JR, Coombs, GH, Milhous, WK, Tzipori, S, Ferguson, DJ, Chakrabarti, D & McLeod, R 1998, 'Evidence for the shikimate pathway in apicomplexan parasites' Nature, vol. 393, no. 6687, pp. 801-805. https://doi.org/10.1038/31723

Evidence for the shikimate pathway in apicomplexan parasites. / Roberts, F; Roberts, C W; Johnson, J J; Kyle, D E; Krell, T; Coggins, J R; Coombs, G H; Milhous, W K; Tzipori, S; Ferguson, D J; Chakrabarti, D; McLeod, R.

In: Nature, Vol. 393, No. 6687, 25.06.1998, p. 801-805.

Research output: Contribution to journalArticle

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T1 - Evidence for the shikimate pathway in apicomplexan parasites

AU - Roberts, F

AU - Roberts, C W

AU - Johnson, J J

AU - Kyle, D E

AU - Krell, T

AU - Coggins, J R

AU - Coombs, G H

AU - Milhous, W K

AU - Tzipori, S

AU - Ferguson, D J

AU - Chakrabarti, D

AU - McLeod, R

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N2 - Parasites of the phylum Apicomplexa cause substantial morbidity, mortality and economic losses, and new medicines to treat them are needed urgently. 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. 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 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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KW - 3-phosphoshikimate 1-carboxyvinyltransferase

KW - alkyl and aryl transferases

KW - amino acid sequence

KW - animals

KW - antiprotozoal agents

KW - cryptosporidium parvum

KW - enzyme inhibitors

KW - glycine

KW - herbicides

KW - molecular sequence data

KW - phosphorus-oxygen lyases

KW - plasmodium falciparum

KW - sequence homology, amino acid

KW - shikimic acid

KW - toxoplasma

U2 - 10.1038/31723

DO - 10.1038/31723

M3 - Article

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SP - 801

EP - 805

JO - Nature

T2 - Nature

JF - Nature

SN - 0028-0836

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ER -

Roberts F, Roberts CW, Johnson JJ, Kyle DE, Krell T, Coggins JR et al. Evidence for the shikimate pathway in apicomplexan parasites. Nature. 1998 Jun 25;393(6687):801-805. https://doi.org/10.1038/31723