Reinvigorating natural product combinatorial biosynthesis with synthetic biology

Kim, Eunji; Moore, Bradley S.; Yoon, Yeo Joon

doi:10.1038/nchembio.1893

Cited by 185 publications

(159 citation statements)

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“…Given that biosynthesis pathways often consist of multiple enzymatic cascades to generate the final products, rational engineering of all the enzymes involved in the pathway may not be the most efficient strategy for non-natural product biosynthesis. Therefore, alternative methods such as directed evolution 42 , mutagenesis 25,43 , pathway recombination 30,44 or semi-synthesis 6,45,46 strategies for generating natural product analogues should be systematically explored in greater detail.…”

Section: Purification Of 7-chloro Analogues Of Violacein and Deoxyviomentioning

confidence: 99%

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

Lai¹,

Obled²,

Chee³

et al. 2017

Preprint

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The next frontier in drug discovery could be the semi-synthesis of non-natural, xenobiotic compounds combining both natural product biosynthesis and synthetic chemistry. However, the required tools and underlying engineering principles are yet to be fully understood. One way to investigate non-natural product biosynthesis is to probe the substrate promiscuity of a clinically relevant biosynthesis pathway. Violacein is a bisindole compound produced by the VioABCDE biosynthesis pathway using L-tryptophan as the starting substrate. Previous studies have shown that violacein exhibits antimicrobial properties, and synthetic analogues of violacein might give rise to new targets for therapeutic development to combat antimicrobial resistance. By adding seven types of tryptophan analogues available commercially, 62 new violacein or deoxyviolacein analogues were generated with a synthetic violacein biosynthesis pathway expressed in Escherichia coli, demonstrating the promiscuity of violacein biosynthesis enzymes. Growth inhibition assays against Bacillus subtilis, a Gram-positive bacterium, were carried out to measure growth inhibitory activity of violacein analogues compared to violacein. In addition, we show that four new 7-chloro analogues of violacein or deoxyviolacein can be generated in vivo by combining the rebeccamycin and violacein biosynthesis pathways and purified 7-chloro violacein was found to have similar growth inhibitory activity compared to violacein. Structural studies of VioA revealed active site residues that are important for catalytic activity, and further pathway recombination with VioA homologues in related bisindole pathways may lead to more efficient enzymes that would accept tryptophan analogues more readily.

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Section: Purification Of 7-chloro Analogues Of Violacein and Deoxyviomentioning

confidence: 99%

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

Lai¹,

Obled²,

Chee³

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…Although still not trivial, the improvement in the past decade in methods for assembling long genetic constructs in a different species host (17), yield optimization by pathway manipulation (18), and combinatorial biosynthesis (19) offer an exciting toolbox for accessing this molecular biodiversity.…”

mentioning

confidence: 99%

Antibiotic discovery is a walk in the park

Nothias

Knight

Dorrestein

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…At the end of this chapter, repurposing PKS for small chemical productions will be discussed, which has been recently spotlighted in the corresponding field. Readers are also encouraged to read through other excellent reviews on polyketides in general [178] and heterologous polyketides production. [10f, 177,179] …”

Section: Introductionmentioning

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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Reinvigorating natural product combinatorial biosynthesis with synthetic biology

Cited by 185 publications

References 100 publications

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

Antibiotic discovery is a walk in the park

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

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