Evidence for the shikimate pathway in apicomplexan parasites.
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.
Roberts
F
F
Michael Reese Hospital and Medical Center, Chicago, Illinois 60616, USA.
Roberts
C W
CW
Johnson
J J
JJ
Kyle
D E
DE
Krell
T
T
Coggins
J R
JR
Coombs
G H
GH
Milhous
W K
WK
Tzipori
S
S
Ferguson
D J
DJ
Chakrabarti
D
D
McLeod
R
R
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D016785:Cryptosporidium parvum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology; D008969:Molecular Sequence Data; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012765:Shikimic Acid / Q000378:metabolism*; D014122:Toxoplasma / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000097797:Glyphosate
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D019883:Alkyl and Aryl Transferases; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D005998:Glycine; D006540:Herbicides; D019761:Phosphorus-Oxygen Lyases; D012765:Shikimic Acid; D000097797:Glyphosate; C019895:chorismate synthase