Engineered biosynthesis of natural products in heterologous hosts

Luo, Yunzi; Li, Bing Zhi; Liu, Duo; Zhang, Lu; Chen, Yan; Jia, Bin; Zeng, Bo; Zhao, Huimin; Yuan, Ying

doi:10.1039/c5cs00025d

Cited by 163 publications

(131 citation statements)

References 192 publications

(411 reference statements)

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“…The production of xantholipin B (1) and xantholipin(2). HPLC profiles of the crude extracts from (a) S. flocculus CGMCC 4.1223 wild-type strain, (b) stnR mutant WJN-1, (c) xantholipin(2)and (d) xantholipin B (1).…”

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confidence: 99%

“…However, the potential secondary metabolite gene clusters far outnumber the secondary metabolites identified because of silent or cryptic biosynthetic gene clusters under classical laboratory conditions in either the native or heterologous hosts, making the discovery of new metabolites quite challenging. [2][3][4] To solve these problems, numerous approaches have been developed to activate silent or cryptic biosynthetic gene clusters. [5][6][7][8] Xantholipin (XAN, 2), a xanthone-derived natural product with a hexacyclic angular fused skeleton, was first isolated from Streptomyces flavogriseus in 2003.…”

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confidence: 99%

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Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Huang

Xie

et al. 2016

J Antibiot

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Xantholipin is a polycyclic xanthone antibiotic that exhibits potent cytotoxic and antibacterial activity. In this study, a new xanthone-type antibiotic, xantholipin B (1), was isolated for the first time along with its known derivative, xantholipin (2), from strain WJN-1, an aminotransferase inactivation mutant of the streptonigrin-producer Streptomyces flocculus CGMCC 4.1223. The structure of 1 was established based on spectroscopic analysis and supports the previously proposed biosynthetic pathway as a key intermediate of 2. Moreover, 1 showed 3- to 10-fold greater cytotoxicity than 2 against a select panel of human cancer cell lines. In addition, 1 demonstrated powerful antimicrobial activity against both Gram-positive bacteria and fungi. Importantly, both 1 and 2 inhibited the methicillin-resistant strain Staphylococcus aureus Mu50, with the MIC value of 0.025 μg ml. The new structural features of 1 enrich the structural diversity of xantholipin family compounds and shed new light on the structure-activity relationship of 1 as a promising antitumor drug candidate.

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confidence: 99%

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confidence: 99%

Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Huang

Xie

et al. 2016

J Antibiot

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“…[7] For these reasons, microorganisms have emerged as alternative platforms for effective production of valuable natural compounds from renewable resources. Recent advances in genetic and metabolic engineering of microorganisms are making it increasingly possible to modify and optimize host microorganisms as designed.…”

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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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“…Heterologous expression has been widely applied as an efficient approach for natural product discovery, optimization of product yield, functional elucidation of cryptic gene clusters, and generation of novel derivatives (14,15). There are a number of potent actinomycete strains which can be used as heterologous expression hosts.…”

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confidence: 99%

High Level of Spinosad Production in the Heterologous Host Saccharopolyspora erythraea

Huang

et al. 2016

Appl Environ Microbiol

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Spinosad, a highly effective insecticide, has an excellent environmental and mammalian toxicological profile. Global market demand for spinosad is huge and growing. However, after much effort, there has been almost no improvement in the spinosad yield from the original producer, Saccharopolyspora spinosa. Here, we report the heterologous expression of spinosad using Saccharopolyspora erythraea as a host. The native erythromycin polyketide synthase (PKS) genes in S. erythraea were replaced by the assembled spinosad gene cluster through iterative recombination. The production of spinosad could be detected in the recombinant strains containing the whole biosynthesis gene cluster. Both metabolic engineering and UV mutagenesis were applied to further improve the yield of spinosad. The final strain, AT-ES04PS-3007, which could produce spinosad with a titer of 830 mg/liter, has significant potential in industrial applications. IMPORTANCEThis work provides an innovative and promising way to improve the industrial production of spinosad. At the same time, it also describes a successful method of heterologous expression for target metabolites of interest by replacing large gene clusters.

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Engineered biosynthesis of natural products in heterologous hosts

Cited by 163 publications

References 192 publications

Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Xantholipin B produced by the stnR inactivation mutant Streptomyces flocculus CGMCC 4.1223 WJN-1

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

High Level of Spinosad Production in the Heterologous Host Saccharopolyspora erythraea

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