Technology development for natural product biosynthesis in Saccharomyces cerevisiae

Billingsley, John M; DeNicola, Anthony B.; Tang, Yi

doi:10.1016/j.copbio.2016.02.033

Cited by 40 publications

(22 citation statements)

References 65 publications

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“…Optimizing nepetalactol production in yeast is therefore a crucial requisite for realizing microbial production of a wide array of high value compounds including iridoids, strictosidine, as well as all downstream MIA natural products. Accordingly, the recent surge in metabolic engineering technologies in yeast has invigorated natural product pathway engineering efforts (Billingsley et al, 2016; Krivoruchko and Nielsen, 2015). …”

Section: Introductionmentioning

confidence: 99%

Engineering the biocatalytic selectivity of iridoid production in Saccharomyces cerevisiae

Billingsley

DeNicola

Barber

et al. 2017

Metabolic Engineering

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Monoterpene indole alkaloids (MIAs) represent a structurally diverse, medicinally essential class of plant derived natural products. The universal MIA building block strictosidine was recently produced in the yeast Saccharomyces cerevisiae, setting the stage for optimization of microbial production. However, the irreversible reduction of pathway intermediates by yeast enzymes results in a non-recoverable loss of carbon, which has a strong negative impact on metabolic flux. In this study, we identified and engineered the determinants of biocatalytic selectivity which control flux towards the iridoid scaffold from which all MIAs are derived. Development of a bioconversion based production platform enabled analysis of the metabolic flux and interference around two critical steps in generating the iridoid scaffold: oxidation of 8-hydroxygeraniol to the dialdehyde 8-oxogeranial followed by reductive cyclization to form nepetalactol. In vitro reconstitution of previously uncharacterized shunt pathways enabled the identification of two distinct routes to a reduced shunt product including endogenous ‘ene’-reduction and non-productive reduction by iridoid synthase when interfaced with endogenous alcohol dehydrogenases. Deletion of five genes involved in α,β-unsaturated carbonyl metabolism resulted in a 5.2-fold increase in biocatalytic selectivity of the desired iridoid over reduced shunt product. We anticipate that our engineering strategies will play an important role in the development of S. cerevisiae for sustainable production of iridoids and MIAs.

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Section: Introductionmentioning

confidence: 99%

Engineering the biocatalytic selectivity of iridoid production in Saccharomyces cerevisiae

Billingsley

DeNicola

Barber

et al. 2017

Metabolic Engineering

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“…Other tools such as the in vitro DNA editing system [23] and the transformation-associated recombination (TAR) method [24 • ] were also established based on the versatile CRISPR/Cas9 system, which further advances technological development in natural product discovery. Successful application of the CRISPR/Cas9 system in fungi has also been reported [25] and reviewed previously [26]. …”

Section: Activation Of Silent Bgcs In Native Hostsmentioning

confidence: 99%

Breaking the silence: new strategies for discovering novel natural products

Ren

Wang

Zhao

2017

Current Opinion in Biotechnology

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Natural products have been a prolific source of antibacterial and anticancer drugs for decades. One of the major challenges in natural product discovery is that the vast majority of natural product biosynthetic gene clusters (BGCs) have not been characterized, partially due to the fact that they are either transcriptionally silent or expressed at very low levels under standard laboratory conditions. Here we describe the strategies developed in recent years (mostly between 2014–2016) for activating silent BGCs. These strategies can be broadly divided into two categories: approaches in native hosts and approaches in heterologous hosts. In addition, we briefly discuss recent advances in developing new computational tools for identification and characterization of BGCs and high-throughput methods for detection of natural products.

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“…Besides, there is an ongoing academic interest for reconstitution of biosynthetic pathways of several natural products, including complex pathways, in S. cerevisiae. Discovery of gene clusters involved in the biosynthesis of secondary metabolites have enhanced progress in microbial production of these molecules [50]. Computational studies have also been conducted to optimize heterologous production in a variety of industrial host microorganisms including S. cerevisiae, which involved application of lux balance analysis on genome-scale models for diferent hosts to identify the optimum host for production [51].…”

Section: Production Of Ine Chemicalsmentioning

confidence: 99%

Advances in Metabolic Engineering of Saccharomyces cerevisiae for the Production of Industrially and Clinically Important Chemicals

Turanlı-Yıldız¹,

Hacısalihoğlu²,

Çakar³

2017

Old Yeasts - New Questions

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Sustainable production of chemicals is of increasing importance, due to depletion of petroleum and environmental concerns. In addition to its importance in basic research as a simple, eukaryotic model organism, Saccharomyces cerevisiae has long been exploited in industry because of its physiological properties. And today, the development in genetic engineering toolbox and genome-scale metabolic models of S. cerevisiae has extended its application range to new products and bioprocesses. In addition, evolutionary engineering strategies have been useful in improving cellular properties of S. cerevisiae, such as tolerance to product toxicity and inhibitors. In this chapter, recent metabolic and evolutionary engineering studies that involve S. cerevisiae for the production of bulk chemicals and ine chemicals including lavours and pharmaceuticals are reviewed. It was shown that metabolic engineering particularly allowed the improvement of pharmaceuticals production, which will enable economic and large-scale production of many valuable pharmaceuticals. It is clear that S. cerevisiae will continue to be an important host for future metabolic engineering and metabolic pathway engineering applications to produce a variety of industrially and clinically important chemicals.

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Technology development for natural product biosynthesis in Saccharomyces cerevisiae

Cited by 40 publications

References 65 publications

Engineering the biocatalytic selectivity of iridoid production in Saccharomyces cerevisiae

Engineering the biocatalytic selectivity of iridoid production in Saccharomyces cerevisiae

Breaking the silence: new strategies for discovering novel natural products

Advances in Metabolic Engineering of Saccharomyces cerevisiae for the Production of Industrially and Clinically Important Chemicals

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