title: Chemical inhibitors suggest endophytic fungal paclitaxel is derived from both mevalonate and non-mevalonate-like pathways.
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.
authors: Department of Plant Agriculture, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
authors: Sameh S M
authors: SS
authors: Soliman
authors: Rong
authors: R
authors: Tsao
authors: Manish N
authors: MN
authors: Raizada
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D008798:Mevalonic Acid / Q000378:metabolism*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D017239:Paclitaxel / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D020946:Taxus / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D009097:Multienzyme Complexes; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; D017239:Paclitaxel; D008798:Mevalonic Acid