Engineering a polyketide with a longer chain by insertion of an extra module into the erythromycin-producing polyketide synthase

Rowe, Christine J.; Böhm, Ines; Thomas, Iain P; Wilkinson, Barrie; Rudd, Brian A. M.; Foster, Graham; Blackaby, Andrew P.; Sidebottom, Philip J.; Roddis, Ylva; Buss, Anthony D; Staunton, James; Leadlay, Peter F.

doi:10.1016/s1074-5521(01)00024-2

Cited by 84 publications

(45 citation statements)

References 34 publications

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“…In 2001, Rowe et al succeeded in producing a new polyketide by inserting rapamycin module 2 between DEBS module 1 and module 2 (Figure 14b). [229] Other examples employing the extender unit exchange were also reported. [207,230] This plug-andplay mode of polyketide biosynthesis by the recombinant PKSs was such a revolution at that time since designing complex compounds by simply recombining different modules had not been possible.…”

Section: Repurposing Pks For Novel Polyketide Biosynthesismentioning

confidence: 99%

“…On the other hand, skipping of modules was also observed, which means that heterologously inserted modules www.advancedsciencenews.com are sometimes ignored by the host PKS machinery as in the production of 1 along with 3 at the right below in Figure 14b. [229] Not only inserting modules in between, but also engineering loading modules [207] or acyltransferases [231] could change the final product by altering the substrate specificity.…”

Section: Repurposing Pks For Novel Polyketide Biosynthesismentioning

confidence: 99%

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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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Section: Repurposing Pks For Novel Polyketide Biosynthesismentioning

confidence: 99%

Section: Repurposing Pks For Novel Polyketide Biosynthesismentioning

confidence: 99%

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

Park

Yang

et al. 2017

Adv. Biosys.

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“…Rowe et al [24] inserted the module 2 of rapamycin PKS (RAPS) into the mutable site of DEBS1-TE, and two novel tetraketides (6 and 7) were produced. Co-expression of the recombinant DEBS1 (RAPS Module 2)-TE with DEBS2 and DEBS3 in Saccharopolyspora erythraea contributed to the formation of four new octaketide macrolactones (9-12) with the normal product erythronolide B (8) (Fig.…”

Section: Strategies Based On Changing the Catalytic Cyclementioning

confidence: 99%

The Combinatorial Biosynthesis of “Unnatural” Products with Polyketides

Zhang

Duan

et al. 2018

Trans. Tianjin Univ.

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Polyketides have been widely used clinically due to their significant biological activities, but the needed structural and functional diversity cannot be achieved by common chemical synthetic methods. The tool of combinatorial biosynthesis provides the possibility to produce "unnatural" natural drugs, which has achieved initial success. This paper provides an overview for the strategies of combinatorial biosynthesis in producing the structural and functional diversity of polyketides, including the redesign of metabolic flow, polyketide synthase (PKS) engineering, and PKS post-translational modification. Although encouraging progress has been made in the last decade, challenges still exist regarding the rational combinatorial biosynthesis of polyketides. In this review, the perspectives of polyketide combinatorial biosynthesis are also discussed.

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“…It has been reported that two novel tetraketides and four octaketides were biosynthesized by combining the rapamycin PKS module with another macrolide erythromycin PKS. 74 Therefore, ongoing studies of the details and mechanisms involving rapamycin biosynthesis and enzymology will be able to generate multiple rapamycin analogs with potential pharmaceutical application.…”

Section: Perspectivesmentioning

confidence: 99%

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

et al. 2010

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Rapamycin and its analogs are clinically important macrolide compounds produced by Streptomyces hygroscopicus. They exhibit antifungal, immunosuppressive, antitumor, neuroprotective and antiaging activities. The core macrolactone ring of rapamycin is biosynthesized by hybrid type I modular polyketide synthase (PKS)/nonribosomal peptide synthetase systems primed with 4,5-dihydrocyclohex-1-ene-carboxylic acid. The linear polyketide chain is condensed with pipecolate by peptide synthetase, followed by cyclization to form the macrolide ring and modified by a series of post-PKS tailoring steps. The aim of this review was to outline past and recent advances in the biosynthesis and regulation of rapamycin, with an emphasis on the distinguished contributions of Professor Demain to the study of rapamycin. In addition, this article describes the biological activities as well as mechanism of action of rapamycin and its derivatives. Recent attempts to improve the productivity of rapamycin and generate diverse rapamycin analogs through mutasynthesis and mutagenesis are also introduced, along with some future perspectives.

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Engineering a polyketide with a longer chain by insertion of an extra module into the erythromycin-producing polyketide synthase

Cited by 84 publications

References 34 publications

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

The Combinatorial Biosynthesis of “Unnatural” Products with Polyketides

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

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