Robertset al. reply
Although our study1 was stimulated by the discovery of the apicomplexan plastid, we did not claim to have provided proof that the shikimate pathway occurred in the plastid in apicomplexans. We believe that the site of this pathway remains an open question, despite the similar data emerging from our own2 and Keeling et al.'s phylogenetic analyses of our chorismate synthase gene sequences.
The premise for the phylogenetic analyses was that if the shikimate pathway occurs in the plastid, then these gene sequences are likely to show evolutionary relatedness to those in green algae, like the genes present on apicomplexan plastid DNA. However, phylogenetic analysis of chorismate synthases in the apicomplexans does not support this hypothesis; rather, it points to a closer similarity with fungal enzymes. From this, Keeling et al. conclude that the shikimate pathway is cytosolic (as it is in fungi).
This situation might have been expected if apicomplexans had evolved directly from a common fungal lineage, but this is not generally believed to be the case. At present, the best evidence available aligns apicomplexans more closely with ciliates and plants, with fungi as distant relatives.
Caution is needed in drawing conclusions about the subcellular locations of proteins from phylogenetic analysis. Such studies are fraught with difficulty because of the frequency with which horizontal gene transfer occurs during evolution, especially when the data are from a relatively small number of organisms. We believe that phylogenetic analysis is an inadequate tool for determining the location(s) of the shikimate pathway in apicomplexans: direct experimental evidence of the location of key proteins is required.
The two apicomplexan chorismate synthases do not have an obvious aminoterminal leader sequence like that found on plastid chorismate synthases of higher plants. However, apicomplexan protein sequences differ from all other reported chorismate synthases in that they have a number of large insertions. The function(s) of these insertions remain(s) unknown, but one of them might act as a targeting sequence, as proteins can be targeted to plastids even without an amino-terminal leader sequence3.
The location of the shikimate pathway in apicomplexan parasites remains an open question. A rigorous, practical approach should reveal that all, some or even none of the shikimate enzymes function within the plastid, or the pathway may turn out to operate both outside and inside the plastid in apicomplexans, as in Euglena4. Irrespective of where the pathway is located, however, it presents a prime target for antiparasitic agents. A cytosolic location would be more accessible to a target enzyme as fewer membranes would need to be crossed.
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Hugosson, M., Nurani, G., Glaser, E. & Franzen, L. -G. Plant Mol. Biol. 28, 525–535 ( 1995).
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Roberts, C., Finnerty, J., Johnson, J. et al. Shikimate pathway in apicomplexan parasites. Nature 397, 220 (1999). https://doi.org/10.1038/16621
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DOI: https://doi.org/10.1038/16621
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