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• W2002355897 abstract "The diterpenoid Taxol (paclitaxel) from the yew (Taxus) species has been used successfully in the treatment of ovarian, breast and lung cancers, as well as of Kaposi's sarcoma. The increased demand for Taxol, coupled with its limited availability from the protected Pacific yew, has had researchers scrambling for alternate sources, including synthetic and semi-synthetic pathways. Its structural complexity, however, has precluded a total synthesis suitable for large-scale production. The biosynthetic route to Taxol is no less intricate than that accomplished in the laboratory: there are a dozen enzymatic steps, including five acyltransferase reactions. Croteau and co-workers at Washington State University have already identified several enzymes in the Taxol biosynthetic pathway, including the first and third acyltransferases. Based on the abundance of naturally occurring taxoids, benzoylation at the taxane C2α-hydroxyl position was expected to be the second acylation step. Now, Walker and Croteau report the cloning from Taxus cuspidata of taxane 2α-O-benzoyltransferase, the enzyme responsible for this acylation reaction 1xTaxol biosynthesis: molecular cloning of a benzoyl-CoA:taxane 2α-O-benzoyltransferase cDNA from Taxus and functional expression in Escherichia coli. Walker, K and Croteau, R. Proc. Natl. Acad. Sci. USA. 2000; 97: 13591–13596Crossref | PubMed | Scopus (101)See all References.The researchers tricked the plant cells into producing more Taxol (and therefore more metabolic enzymes) by incubation with methyl jasmonate, a plant signaling molecule involved in environmental stress responses. Several potential clones were isolated using transacylase-specific primers, and these clones exhibited high (64–72%) sequence similarity to previously identified enzymes in the family. Putative constructs were expressed in Escherichia coli and isolated, then evaluated for their ability to use radiolabeled benzoyl-CoA in a transferase reaction. The natural diterpenoid substrate was not available in sufficient quantities to assay the expressed protein, so 2-debenzoyl-7,13-diacetylbaccatin III was prepared semisynthetically. Upon incubation with the soluble enzyme fraction, a biosynthetic product corresponding to authentic 7,13-diacetylbaccatinIII was identified. Product formation was regioselective for the 2α-hydroxyl position and dependent on a high level of ring substitution. The functional benzoyltransferase is a 440-residue protein with over 60% sequence identity to the other two acyltransferases in the Taxol pathway, and contains the previously identified HXXXDG motif that might contribute to acyl group transfer.Taxol achieves its anticancer activity by a novel mechanism: it promotes the assembly of tubulin into microtubules, thereby disrupting mitosis. Taxol resistance is already a problem in several tumor lines, and seems due in part to changes in post-translational modifications of tubulin. Structure–function studies of Taxol have suggested that the C2 benzoate moiety is necessary for tubulin stabilization, and that substitutions at this position could yield taxol derivatives with enhanced potency. Taxane 2α-O-benzoyltransferase might provide an enzymatic means for enhanced production of Taxol and new anticancer drugs derived from this remarkable plant product." @default.
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• W2002355897 date "2001-03-01" @default.
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• W2002355897 title "Teasing apart the Taxol pathway" @default.
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• W2002355897 doi "https://doi.org/10.1016/s0968-0004(00)01762-x" @default.
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