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Taxol Biosynthesis and Molecular Genetics

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Abstract

Biosynthesis of the anticancer drug Taxol in Taxus (yew) species involves 19 steps from the universal diterpenoid progenitor geranylgeranyl diphosphate derived by the plastidial methyl erythritol phosphate pathway for isoprenoid precursor supply. Following the committed cyclization to the taxane skeleton, eight cytochrome P450-mediated oxygenations, three CoA-dependent acyl/aroyl transfers, an oxidation at C9, and oxetane (D-ring) formation yield the intermediate baccatin III, to which the functionally important C13-side chain is appended in five additional steps. To gain further insight about Taxol biosynthesis relevant to the improved production of this drug, and to draw inferences about the organization, regulation, and origins of this complex natural product pathway, Taxus suspension cells (induced for taxoid biosynthesis by methyl jasmonate) were used for feeding studies, as the foundation for cell-free enzymology and as the source of transcripts for cDNA library construction and a variety of cloning strategies. This approach has led to the elucidation of early and late pathway segments, the isolation and characterization of over half of the pathway enzymes and their corresponding genes, and the identification of candidate cDNAs for the remaining pathway steps, and it has provided many promising targets for genetically engineering more efficient biosynthetic production of Taxol and its precursors.

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Abbreviations

DD-RT-PCR:

differential display of mRNA-reverse transcription-polymerase chain reaction

DMAPP:

dimethylallyl diphosphate

DXP:

1-deoxy-d-xylulose-5-phosphate

EST:

expressed sequence tags

GGPP:

geranylgeranyl diphosphate

GGPPS:

geranylgeranyl diphosphate synthase

IPP:

isopentenyl diphosphate

IPPI:

isopentenyl diphosphate isomerase

MEP:

2-C-methyl-d-erythritol phosphate

NMR:

nuclear magnetic resonance spectroscopy

PAM:

phenylalanine aminomutase

TS:

taxadiene synthase

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Authors and Affiliations

  1. Institute of Biological Chemistry, Washington State University, Pullman, WA, 99164-6340, USA

    Rodney Croteau, Raymond E. B. Ketchum, Robert M. Long, Rüdiger Kaspera & Mark R. Wildung

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  1. Rodney Croteau
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  2. Raymond E. B. Ketchum
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  3. Robert M. Long
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  4. Rüdiger Kaspera
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  5. Mark R. Wildung
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Correspondence to Rodney Croteau.

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Croteau, R., Ketchum, R.E.B., Long, R.M. et al. Taxol Biosynthesis and Molecular Genetics. Phytochem Rev 5, 75–97 (2006). https://doi.org/10.1007/s11101-005-3748-2

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