Taxol® Biosynthesis and Production: From Forests to Fermenters

McElroy, Christopher; Jennewein, Stefan

doi:10.1007/978-3-319-67903-7_7

Cited by 42 publications

(34 citation statements)

References 200 publications

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“…Taxol is formed by a tetracyclic oxaheptadecane skeleton decorated with eight functional oxygen groups, two acyl groups, and a benzyl group [280]. After the elucidation of its structure in 1971 [277], several clinical trials led to its approval by the FDA as an anticancer drug for the treatment of a wide range of cancers (ovarian, breast, lung, Kaposiʼs sarcoma, cervical, and pancreatic) [281].…”

Section: Taxolmentioning

confidence: 99%

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The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

et al. 2018

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Plants have always been used as medicines since ancient times to treat diseases. The knowledge around the active components of herbal preparations has remained nevertheless fragmentary: the biosynthetic pathways of many secondary metabolites of pharmacological importance have been clarified only in a few species, while the chemodiversity present in many medicinal plants has remained largely unexplored. Despite the advancements of synthetic biology for production of medicinal compounds in heterologous hosts, the native plant species are often the most reliable and economic source for their production. It thus becomes fundamental to investigate the metabolic composition of medicinal plants to characterize their natural metabolic diversity and to define the biosynthetic routes of important compounds to develop strategies to further increase their content. We present here a number of case studies for selected classes of secondary metabolites and we review their health benefits and the historical developments in their structural elucidation and characterization of biosynthetic genes. We cover the cases of benzoisoquinoline and monoterpenoid indole alkaloids, cannabinoids, caffeine, ginsenosides, withanolides, artemisinin, and taxol; we show how the "early" biochemical or the more recent integrative approaches-based on omics-analyses-have helped to elucidate their metabolic pathways and cellular compartmentation. We also summarize how the knowledge generated about their biosynthesis has been used to develop metabolic engineering strategies in heterologous and native hosts. We conclude that following the advent of novel, high-throughput and cost-effective analytical technologies, the secondary metabolism of medicinal plants can now be examined under the lens of systems biology.

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Section: Taxolmentioning

confidence: 99%

“…In addition to that, the knowledge of the pathway of taxol biosynthesis remains incomplete. Of the 20 hypothesized enzymatic steps, only 14 have been well characterized [280,284,285] (▶ Fig. 9).…”

Section: Taxolmentioning

confidence: 99%

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

et al. 2018

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“…The highly complex diterpenoid drug Paclitaxel (Taxol™) first gained FDA approval in 1992 62 for the treatment of ovarian cancer and has since proven efficacious against a wide range of 63 additional diseases (McElroy and Jennewein, 2018). Direct extraction from its natural source, the 64 bark of Pacific yew (Taxus brevifolia), is both destructive and extremely low-yielding.…”

mentioning

confidence: 99%

Enhanced production of taxadiene in Saccharomyces cerevisiae

Nowrouzi

Walls

et al. 2020

Preprint

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Metabolic Engineering 23Highlights 27• Maximum taxadiene titre of 129 ± 15 mg/L in Saccharomyces cerevisiae at 20 °C 28• Integrating fusion protein tagged-taxadiene synthase improved taxadiene titre. 29• Consistent taxadiene titres were achieved at the micro-and mini-bioreactor scales. 30 Abstract 31Cost-effective production of the highly effective anti-cancer drug, paclitaxel (Taxol®), remains 32 limited despite growing global demands. Low yields of the critical taxadiene precursor remains a 33 key bottleneck in microbial production. In this study, the key challenge of poor taxadiene synthase 34 (TASY) solubility in S. cerevisiae was revealed, and the strains were strategically engineered to 35 relieve this bottleneck. Multi-copy chromosomal integration of TASY harbouring a selection of 36 fusion solubility tags improved taxadiene titres 22-fold, up to 57 ± 3 mg/L at 30 °C at shake flask 37 scale. The scalability of the process was highlighted through achieving similar titres during scale 38 up to 25 mL and 250 mL in shake flask and bioreactor cultivations, respectively. Maximum 39 taxadiene titres of 129 ± 15 mg/L and 119 mg/L were achieved through shake flask and bioreactor 40 cultivation, respectively, of the optimal strain at a reduced temperature of 20 °C. The results 41 highlight the positive effect of coupling molecular biology tools with bioprocess variable 42 optimisation on synthetic pathway development. 43 44 Abbreviations 45 46 BTS1, Geranylgeranyl diphosphate synthase; crtE, Geranylgeranyl diphosphate synthase; 47 DMAPP, Dimethylallyl pyrophosphate; ERG8, Phosphomevalonate kinase; ERG9, Farnesyl-48 iv diphosphate farnesyl transferase (squalene synthase); ERG10, 3-hydroxy-3-methylglutaryl-CoA 49 (HMG-CoA) synthase; ERG12, Mevalonate kinase; ERG13, 3-hydroxy-3-methylglutaryl-CoA 50 (HMG-CoA) synthase; ERG19, Mevalonate pyrophosphate decarboxylase; ERG20, Farnesyl 51 pyrophosphate synthetase; FPP, Farnesyl diphosphate; GGOH, (E,E,E)-geranylgeraniol; GGPP, 52 (E,E,E)-Geranylgeranyl diphosphate; GPP, Geranyl diphosphate; HMG1, 3-hydroxy-3-53 methylglutaryl-coenzyme A reductase 1; HMG2, 3-hydroxy-3-methylglutaryl-coenzyme 54 A reductase 2; IDI, Isopentenyl-diphosphate delta-isomerase; IPP, Isopentenyl pyrophosphate; 55 MBP, Maltose binding protein; mvaE, Acetyl-CoA acetyltransferase; mvaS, 56 Hydroxymethylglutaryl-CoA synthase; MVA pathway, Mevalonate pathway; TASY, Taxadiene 57 synthase 58 59 60

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“…Another high‐potential area is to deepen our understanding of what therapeutics and other useful specialized metabolites, plants, and their associated biota might provide; one example is synthetic biology production of artemisinin, an ancient Chinese herbal remedy, as a malarial therapeutic (Ikram & Simonsen, 2017; Peplow, 2016). High‐throughput screening (Atanasov et al., 2015) of plant compounds produced paclitaxel (the cancer medication Taxol; McElroy et al., 2018; Rowinsky & Donehower, 1995), but development of screening tools with much higher accuracy and throughput is needed for health science and other applications. Novel developments may also be expected from investigations of how plant‐associated organisms, especially microbes, contribute to and influence plant metabolic phenotypes.…”

Section: Recommendationsmentioning

confidence: 99%

“…Chief among these are therapeutics derived from plant chemistry. Paclitaxel (Taxol), which is used for cancer treatment, is one recent example (McElroy & Jennewein, 2018; Rowinsky & Donehower, 1995), but there are hundreds of other herbal remedies in use, many of which have indigenous origins and whose scientific basis remains little explored.…”

Section: Introductionmentioning

confidence: 99%

Plant science decadal vision 2020–2030: Reimagining the potential of plants for a healthy and sustainable future

et al. 2020

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Plants, and the biological systems around them, are key to the future health of the planet and its inhabitants. The Plant Science Decadal Vision 2020–2030 frames our ability to perform vital and far‐reaching research in plant systems sciences, essential to how we value participants and apply emerging technologies. We outline a comprehensive vision for addressing some of our most pressing global problems through discovery, practical applications, and education. The Decadal Vision was developed by the participants at the Plant Summit 2019, a community event organized by the Plant Science Research Network. The Decadal Vision describes a holistic vision for the next decade of plant science that blends recommendations for research, people, and technology. Going beyond discoveries and applications, we, the plant science community, must implement bold, innovative changes to research cultures and training paradigms in this era of automation, virtualization, and the looming shadow of climate change. Our vision and hopes for the next decade are encapsulated in the phrase reimagining the potential of plants for a healthy and sustainable future. The Decadal Vision recognizes the vital intersection of human and scientific elements and demands an integrated implementation of strategies for research (Goals 1–4), people (Goals 5 and 6), and technology (Goals 7 and 8). This report is intended to help inspire and guide the research community, scientific societies, federal funding agencies, private philanthropies, corporations, educators, entrepreneurs, and early career researchers over the next 10 years. The research encompass experimental and computational approaches to understanding and predicting ecosystem behavior; novel production systems for food, feed, and fiber with greater crop diversity, efficiency, productivity, and resilience that improve ecosystem health; approaches to realize the potential for advances in nutrition, discovery and engineering of plant‐based medicines, and "green infrastructure." Launching the Transparent Plant will use experimental and computational approaches to break down the phytobiome into a "parts store" that supports tinkering and supports query, prediction, and rapid‐response problem solving. Equity, diversity, and inclusion are indispensable cornerstones of realizing our vision. We make recommendations around funding and systems that support customized professional development. Plant systems are frequently taken for granted therefore we make recommendations to improve plant awareness and community science programs to increase understanding of scientific research. We prioritize emerging technologies, focusing on non‐invasive imaging, sensors, and plug‐and‐play portable lab technologies, coupled with enabling computational advances. Plant systems science will benefit from data management and future advances in automation, machine learning, natural language processing, and artificial intelligence‐assisted data integration, pattern identification, and decision making. Implementation of th...

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Taxol® Biosynthesis and Production: From Forests to Fermenters

Cited by 42 publications

References 200 publications

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

Enhanced production of taxadiene in Saccharomyces cerevisiae

Plant science decadal vision 2020–2030: Reimagining the potential of plants for a healthy and sustainable future

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