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Chemical Inhibitors Suggest Endophytic Fungal Paclitaxel Is Derived from Both Mevalonate and Non-mevalonate-like Pathways
Faculty
Pharmacy
Year:
2011
Type of Publication:
Article
Pages:
2497-2504
Authors:
Soliman, Sameh S. M, Tsao, Rong, Raizada, Manish N
DOI:
10.1021/np200303v
Journal:
JOURNAL OF NATURAL PRODUCTS AMER CHEMICAL SOC
Volume:
74
Research Area:
Plant Sciences; Pharmacology \& Pharmacy
ISSN
ISI:000298315800002
Keywords :
Chemical Inhibitors Suggest Endophytic Fungal Paclitaxel
Abstract:
Taxus trees possess fungal endophytes reported to produce paclitaxel. Inhibitors that block early steps in plant paclitaxel biosynthesis were applied to a paclitaxel-producing fungus to determine whether these steps are shared. The plant paclitaxel backbone is reportedly derived from the non-mevalonate terpenoid pathway, while the side chain is phenylalanine-derived. Evidence that the shikimate pathway contributes to fungal paclitaxel was shown by decreased paclitaxel accumulation following inhibition of phenylalanine ammonia lyase. Expression of another shikimate pathway enzyme, 3-dehydroquinate synthase, coincided with paclitaxel production. The importance of the mevalonate pathway in fungal paclitaxel biosynthesis was shown by inhibition of fungal paclitaxel accumulation using compactin, a specific inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase. Expression of another mevalonate pathway enzyme, 3-hydroxy-3-methyl-glutaryl-CoA synthase, coincided with fungal paclitaxel accumulation. Unexpectedly, results from using fosmidomycin suggested that fungal paclitaxel requires 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an enzyme in the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway normally found in bacteria/plants. Additional lines of evidence support this finding; first, a plant DXR antibody recognized a fungal peptide of the correct size; second, expression of an apparent fungal DXR ortholog correlated to changes in paclitaxel production; finally, BLAST searching identified a gene putatively encoding 1-deoxy-D-xylulose-5-phosphate synthase, the first enzyme in the MEP pathway in Aspergillus.
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