Downstream reactions and engineering in the microbially reconstituted pathway for Taxol

Jiang, Ming; Stephanopoulos, Gregory; Pfeifer, Blaine A.

doi:10.1007/s00253-012-4016-1

Cited by 37 publications

(28 citation statements)

References 73 publications

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“…The diterpenoid paclitaxel—commercialized as taxol—from yew tree bark is a potent cytostatic drug for cancer treatment 182. Current semisynthetic production combines cell culture based Baccatin III production with subsequent chemical conversion.…”

Section: Health and Nutritionmentioning

confidence: 99%

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Advanced Biotechnology: Metabolically Engineered Cells for the Bio‐Based Production of Chemicals and Fuels, Materials, and Health‐Care Products

2015

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Corynebacterium glutamicum, Escherichia coli, and Saccharomyces cerevisiae in particular, have become established as important industrial workhorses in biotechnology. Recent years have seen tremendous progress in their advance into tailor-made producers, driven by the upcoming demand for sustainable processes and renewable raw materials. Here, the diversity and complexity of nature is simultaneously a challenge and a benefit. Harnessing biodiversity in the right manner through synergistic progress in systems metabolic engineering and chemical synthesis promises a future innovative bio-economy.

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Section: Health and Nutritionmentioning

confidence: 99%

“…Both S. cerevisiae and E. coli have been used to generate early stage intermediates of the biosynthetic paclitaxel pathway 8a,c. 24a, 182, 183 Production now surpasses the gram scale, thus encouraging further engineering for process optimization 8a…”

Section: Health and Nutritionmentioning

confidence: 99%

Advanced Biotechnology: Metabolically Engineered Cells for the Bio‐Based Production of Chemicals and Fuels, Materials, and Health‐Care Products

2015

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“…Beyond their essential cellular functions, terpenoids have great commercial value to serve as pharmaceuticals (Ajikumar et al, 2010;Anthony et al, 2009;Jiang et al, 2012;Ro et al, 2006) and nutriceuticals (Miura et al, 1998). Traditionally, these valuable terpenoids are extracted from their natural sources but this procedure is laborious and expensive due to the low abundance of these compounds in their natural host (Ishida and Chapman, 2009;Lapkin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial engineering of mevalonate pathway for improved amorpha‐4,11‐diene production in budding yeast

Yuan

Ching

2013

Biotech & Bioengineering

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Combinatorial genome integration of mevalonate pathway genes was performed with the aim of optimizing the metabolic flux for improved production of terpenoids in budding yeast. In the present study, we developed a novel δ-integration platform to achieve multiple genome integrations through modulating the concentration of antibiotics. By exploiting carotenoid biosynthesis as screening module, we successfully created a library of yeast colonies appeared with various intensities of orange color. As proof-of-concept that carotenoid overproducers could serve to boost the titer of other terpenoids, we further tested engineered strains for the production of amorpha-4,11-diene, an important precursor for antimalarial drug. However, we experienced some limitations of the carotenoid-based screening approach as it was only effective in detecting a small range of pathway activity improvement and further increasing mevalonate pathway activity led to a decreased orange color. By far, we were only able to obtain one mutant strain yielded more than 13-fold amorpha-4,11-diene over parental strains, which was approximately 64 mg/L of caryophyllene equivalents. Further qPCR studies confirmed that erg10, erg13, thmg1 and erg12 involved in mevalonate pathway were overexpressed in this mutant strain. We envision the current δ-integration platform would form the basis of a generalized technique for multiple gene integrations in yeast-a method that would be of significant interest to the metabolic engineering community.

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“…Solutions to these issues may be found with improved agricultural or biotechnological production systems. For example, production of taxol uses combinations of precursors isolated from foliage of cultivated Taxus species, semisynthesis, and plant cell cultures (Jiang et al, 2012;Wilson and Roberts, 2012). Alternatively, microbial metabolic engineering and synthetic biology approaches are being explored for production of high-value diterpenes (Ajikumar et al, 2010;Caniard et al, 2012;Schalk et al, 2012;Zerbe et al, 2012a;Zhou et al, 2012b).…”

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confidence: 99%

Gene Discovery of Modular Diterpene Metabolism in Nonmodel Systems

et al. 2013

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(Bj.H., Br.H., S.S.B.)Plants produce over 10,000 different diterpenes of specialized (secondary) metabolism, and fewer diterpenes of general (primary) metabolism. Specialized diterpenes may have functions in ecological interactions of plants with other organisms and also benefit humanity as pharmaceuticals, fragrances, resins, and other industrial bioproducts. Examples of high-value diterpenes are taxol and forskolin pharmaceuticals or ambroxide fragrances. Yields and purity of diterpenes obtained from natural sources or by chemical synthesis are often insufficient for large-volume or high-end applications. Improvement of agricultural or biotechnological diterpene production requires knowledge of biosynthetic genes and enzymes. However, specialized diterpene pathways are extremely diverse across the plant kingdom, and most specialized diterpenes are taxonomically restricted to a few plant species, genera, or families. Consequently, there is no single reference system to guide gene discovery and rapid annotation of specialized diterpene pathways. Functional diversification of genes and plasticity of enzyme functions of these pathways further complicate correct annotation. To address this challenge, we used a set of 10 different plant species to develop a general strategy for diterpene gene discovery in nonmodel systems. The approach combines metabolite-guided transcriptome resources, custom diterpene synthase (diTPS) and cytochrome P450 reference gene databases, phylogenies, and, as shown for select diTPSs, single and coupled enzyme assays using microbial and plant expression systems. In the 10 species, we identified 46 new diTPS candidates and over 400 putatively terpenoid-related P450s in a resource of nearly 1 million predicted transcripts of diterpene-accumulating tissues. Phylogenetic patterns of lineage-specific blooms of genes guided functional characterization.

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Downstream reactions and engineering in the microbially reconstituted pathway for Taxol

Cited by 37 publications

References 73 publications

Advanced Biotechnology: Metabolically Engineered Cells for the Bio‐Based Production of Chemicals and Fuels, Materials, and Health‐Care Products

Advanced Biotechnology: Metabolically Engineered Cells for the Bio‐Based Production of Chemicals and Fuels, Materials, and Health‐Care Products

Combinatorial engineering of mevalonate pathway for improved amorpha‐4,11‐diene production in budding yeast

Gene Discovery of Modular Diterpene Metabolism in Nonmodel Systems

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