The Chemistry of Taxol and Related Taxoids

Kingston, David G. I.; Jagtap, Prakash G.; Yuan, Haiqing; Samala, Lakshman

doi:10.1007/978-3-7091-6160-9_2

Cited by 48 publications

(51 citation statements)

References 451 publications

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“…It was originally isolated as a bioactive component from the bark of Pacific yew (Taxus brevifolia; Suffness and Wall 1995), and later structurally defined as a very complex multi-substituted taxane diterpenoid (Wani et al 1971). Extremely low levels of paclitaxel in slow-growing Pacific yews (*0.015% dry weight; Vidensek et al 1990), prompted several laboratories to develop chemical methods to totally synthesize paclitaxel (reviewed in Kingston et al 2002), but none of these methods are suitable for large-scale commercial production of the drug. Paclitaxel is currently manufactured from an advanced paclitaxel precursor 10-deacetylbaccatin III (Holton et al 1995), which is extracted from needles of European yew (Taxus baccata; Chauviere et al 1981).…”

Section: Introductionmentioning

confidence: 99%

Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens

et al. 2009

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Taxadiene synthase gene from Taxus brevifolia was constitutively expressed in the moss Physcomitrella patens using a ubiquitin promoter to produce taxa-4(5),11(12)-diene, the precursor of the anticancer drug paclitaxel. In stable moss transformants, taxa-4(5),11(12)-diene was produced up to 0.05% fresh weight of tissue, without significantly affecting the amounts of the endogenous diterpenoids (ent-kaurene and 16-hydroxykaurane). Unlike higher plants that had been genetically modified to produce taxa-4(5),11(12)-diene, transgenic P. patens did not exhibit growth inhibition due to alteration of diterpenoid metabolic pools. Thus we propose that P. patens is a promising alternative host for the biotechnological production of paclitaxel and its precursors.

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Section: Introductionmentioning

confidence: 99%

Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens

et al. 2009

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“…The closely related drug Taxotere (generic name docetaxel; Figure 1) is prepared semi-synthetically from 10-deacetyl baccatin III. Several elegant total syntheses of Taxol have been devised (reviewed in Kingston et al, 2002;Xiao et al, 2003), but this approach is not commercially viable due to low yield and high cost considerations. With the increasing utilization of Taxol for the treatment of additional cancer types and other human diseases, for application much earlier in the course of intervention, for combination therapies with other antineoplastic agents (e.g., with anthracyclines and platinum compounds) (Goldspiel, 1997;Brown, 2003), and as the platform for the development of the next generation of more efficacious drugs and prodrugs (Wang et al, 2003), the market for Taxol and its congeners is expected to expand by threefold within the next 4 years (McCoy, 2004).…”

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confidence: 99%

Taxol Biosynthesis and Molecular Genetics

et al. 2006

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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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“…Although the total synthesis of Taxol has been achieved (Kingston et al 2002), the approach is too expensive for it being commercially practical (Borman 1994). The drug is produced by yew ( Taxus ) species in about 19 individual enzymatic steps from the isoprenoid precursor geranylgeranyl diphosphate (Jennewein and Croteau 2001; Walker and Croteau 2001).…”

Section: Biosynthesis Of Pharmaceuticalsmentioning

confidence: 99%

Synthetic biology approaches in drug discovery and pharmaceutical biotechnology

Neumann

Neumann‐Staubitz

2010

Appl Microbiol Biotechnol

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Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology.

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The Chemistry of Taxol and Related Taxoids

Cited by 48 publications

References 451 publications

Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens

Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens

Taxol Biosynthesis and Molecular Genetics

Synthetic biology approaches in drug discovery and pharmaceutical biotechnology

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