Microbial biosynthesis of the anticoagulant precursor 4-hydroxycoumarin

Lin, Yuheng; Shen, Xiaolin; Yuan, Qipeng; Yan, Yajun

doi:10.1038/ncomms3603

Cited by 136 publications

(84 citation statements)

References 47 publications

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“…However, increasing concerns on environmental issues have stimulated efforts towards the development of biological processes capable of utilizing renewable resources (Lin et al 2013a). Several bacteria and fungi are known to synthesize coumarin (Aslam et al 2010;Nikhil et al 2012;Rohini and Srikumar 2014), e.g., Agaricus sp.…”

Section: Introductionmentioning

confidence: 99%

“…Significant advances in synthetic bioengineering, metabolic engineering, and bioinformatics have promoted the modified biosynthesis of a variety of pharmaceutically important compounds in heterologous microbial host. This allowed wider applications of these compounds on an industrial scale (Vannelli et al 2007;Lin et al 2013a;Hara et al 2014). In this context, we presented an overview of the potential of fungi as coumarin producer and their biological applications besides the properties, characteristics, production, and biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

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Fungi as a source of natural coumarins production

Costa

Tavares

Oliveira

2016

Appl Microbiol Biotechnol

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Natural coumarins and derivatives are compounds that occur naturally in several organisms (plant, bacteria, and fungi) consisting of fused benzene and α-pyrone rings. These compounds show high technological potential applications in agrochemical, food, pharmaceuticals, and cosmetics industries. Therefore, the need for bulk production of coumarins and the advancement of the chemical and pharmaceutical industries led to the development of synthetic coumarin. However, biotransformation process, synthetic bioengineering, metabolic engineering, and bioinformatics have proven effective in the production of natural products. Today, these biological systems are recognized as green chemistry innovation and business strategy. This review article aims to report the potential of fungi for synthesis of coumarin. These microorganisms are described as a source of natural products capable of synthesizing many bioactive metabolites. The features, classification, properties, and industrial applications of natural coumarins as well as new molecules obtained by basidiomycetes and ascomycetes fungi are reported in order to explore a topic not yet discussed in the scientific literature.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fungi as a source of natural coumarins production

Costa

Tavares

Oliveira

2016

Appl Microbiol Biotechnol

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“…One important synthetic chemistry reaction endowed by nature is the decarboxylative carbon condensation reaction using malonyl-CoA as carbon donor (29). Previous metabolic engineering efforts centered on malonyl-CoA-dependent pathways have resulted in the production of many value-added compounds including fatty acids (21), phenylpropanoids (45,46), and polyketides (47). Here we mimicked the native biological systems and used a dynamic regulatory network to optimize production titers and yield.…”

Section: −1mentioning

confidence: 99%

Improving fatty acids production by engineering dynamic pathway regulation and metabolic control

Zhang

et al. 2014

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

449

358

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Global energy demand and environmental concerns have stimulated increasing efforts to produce carbon-neutral fuels directly from renewable resources. Microbially derived aliphatic hydrocarbons, the petroleum-replica fuels, have emerged as promising alternatives to meet this goal. However, engineering metabolic pathways with high productivity and yield requires dynamic redistribution of cellular resources and optimal control of pathway expression. Here we report a genetically encoded metabolic switch that enables dynamic regulation of fatty acids (FA) biosynthesis in Escherichia coli. The engineered strains were able to dynamically compensate the critical enzymes involved in the supply and consumption of malonyl-CoA and efficiently redirect carbon flux toward FA biosynthesis. Implementation of this metabolic control resulted in an oscillatory malonyl-CoA pattern and a balanced metabolism between cell growth and product formation, yielding 15.7-and 2.1-fold improvement in FA titer compared with the wild-type strain and the strain carrying the uncontrolled metabolic pathway. This study provides a new paradigm in metabolic engineering to control and optimize metabolic pathways facilitating the high-yield production of other malonyl-CoA-derived compounds.biofuels | dynamic metabolic control | transcriptional regulation A grand challenge in synthetic biology is to move the design of biomolecular circuits from purely genetic constructs toward systems that integrate different levels of cellular complexity, including regulatory networks and metabolic pathways (1). Despite the fact that a large volume of regulatory architectures and motifs has been discovered (2, 3), little has been accomplished in pathway engineering to improve cellular productivity and yield by exploiting dynamic pathway regulation and metabolic control (4). One essential part in implementing synthetic metabolic control in pathway engineering is to engineer novel metabolite sensors with desired input-output relationships. For example, have designed and applied a regulatory circuit that can sense the glycolytic pathway hallmark metabolite acetylphosphate to control the lycopene biosynthetic pathway (5) and generate oscillatory gene expression (6) as well as achieve artificial cell-cell communication (7). Dahl et al. (8) have used stressresponse promoters to improve farnesyl pyrophosphate production, and Tsao et al. (9) have rewired the Escherichia coli native quorumsensing regulon for autonomous induction of recombinant proteins.Traditional metabolic engineering is largely focused on the overexpression of rate-limiting steps (10

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“…Metabolic engineering approaches have previously been developed for the production of valuable natural plant coumarins in E. coli 19, 20, 21. However, as far as we are aware, this is the first example of the production of a “non‐natural” halogenated coumarin from glucose in E. coli .…”

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confidence: 98%

RadH: A Versatile Halogenase for Integration into Synthetic Pathways

et al. 2017

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Flavin‐dependent halogenases are useful enzymes for providing halogenated molecules with improved biological activity, or intermediates for synthetic derivatization. We demonstrate how the fungal halogenase RadH can be used to regioselectively halogenate a range of bioactive aromatic scaffolds. Site‐directed mutagenesis of RadH was used to identify catalytic residues and provide insight into the mechanism of fungal halogenases. A high‐throughput fluorescence screen was also developed, which enabled a RadH mutant to be evolved with improved properties. Finally we demonstrate how biosynthetic genes from fungi, bacteria, and plants can be combined to encode a new pathway to generate a novel chlorinated coumarin “non‐natural” product in E. coli.

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Microbial biosynthesis of the anticoagulant precursor 4-hydroxycoumarin

Cited by 136 publications

References 47 publications

Fungi as a source of natural coumarins production

Fungi as a source of natural coumarins production

Improving fatty acids production by engineering dynamic pathway regulation and metabolic control

RadH: A Versatile Halogenase for Integration into Synthetic Pathways

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