The early stages of taxol biosynthesis: An interim report on the synthesis and identification of early pathway metabolites

Guerra-Bubb, Jennifer M.; Croteau, Rodney; Williams, Robert M.

doi:10.1039/c2np20021j

Cited by 77 publications

(72 citation statements)

References 91 publications

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“…These few include the biosyntheses of taxol in Taxus spp. (Walker and Croteau, 2001;Guerra-Bubb et al, 2012), diterpene resin acids in a few conifers (Hamberger et al, 2011;Keeling et al, 2011a;Zerbe et al, 2012a;Hall et al, 2013), and diterpene defense compounds in rice and wheat (Xu et al, 2007a;Wu et al, 2012;Zhou et al, 2012a). In addition, individual enzymes of specialized diterpene biosynthesis, in particular different diTPS genes, have been functionally characterized in approximately a dozen different species.…”

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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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confidence: 99%

Gene Discovery of Modular Diterpene Metabolism in Nonmodel Systems

et al. 2013

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“…Chemical synthesis of taxol has been difficult because of its complex chemical structure [102] while its microbial production was also difficult for its unusually long biosynthetic pathway. [103] Therefore, the intermediates of taxol such as taxadiene and oxygenated taxanes were biosynthesized by metabolically engineered E. coli [104] or yeast, [105] which then went through chemical processes for the final product synthesis.…”

Section: Semi-synthesis Processmentioning

confidence: 99%

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

Park

Yang

et al. 2017

Adv. Biosys.

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Natural products have been attracting much interest around the world for their diverse applications, especially in drug and food industries. Plants have been a major source of many different natural products. However, plants are affected by weather and environmental conditions and their successful extraction is rather limited. Chemical synthesis is inefficient due to the complexity of their chemical structures involving enantioselectivity and regioselectivity. For these reasons, an alternative means of overproducing valuable natural products using microorganisms has emerged. In recent years, various metabolic engineering strategies have been developed for the production of natural products by microorganisms. Here, the strategies taken to produce natural products are reviewed. For convenience, natural products are classified into four main categories: terpenoids, phenylpropanoids, polyketides, and alkaloids. For each product category, the strategies for establishing and rewiring the metabolic network for heterologous natural product biosynthesis, systems approaches undertaken to optimize production hosts, and the strategies for fermentation optimization are reviewed. Taken together, metabolic engineering has enabled microorganisms to serve as a prominent platform for natural compounds production. This article examines both the conventional and novel strategies of metabolic engineering, providing general strategies for complex natural compound production through the development of robust microbial‐cell factories.

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“…While a high concentration of precursors may usually increase reaction rates, the toxicity to cells may also increase with increase in concentration, and so the concentration of precursor to be added to an endophytic fungal culture has to be optimized carefully (Gaosheng and Jingming, 2012). Precursor feeding studies have also played a major part in the elucidation of biosynthetic pathways of various metabolites including taxol and camptothecin (Guerra-Bubb et al, 2012;Yamazaki et al, 2004). Stierle et al (1993) used isotope-labeled precursors to establish the existence of taxol biosynthetic machinery in the fungal culture, T. andreanae.…”

Section: Precursor Feedingmentioning

confidence: 99%