Synbiological systems for complex natural products biosynthesis

Li, Jianhua; Meng, Hailin; Wang, Yong

doi:10.1016/j.synbio.2016.08.002

Cited by 4 publications

(3 citation statements)

References 73 publications

(112 reference statements)

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“…Multimodular metabolic engineering is an efficient strategy for addressing perturbances such as imbalance in pathway flux, module incompatibility or accumulation of intermediates caused by manipulation of endogenous genes and the introduction of heterologous pathways, and this method enables systematic manipulation of strains and metabolic pathways [24, 25]. This potential strategy has been widely implemented in Escherichia coli and S. cerevisiae for the production of value-added compounds.…”

Section: Introductionmentioning

confidence: 99%

Boosting the biosynthesis of betulinic acid and related triterpenoids in Yarrowia lipolytica via multimodular metabolic engineering

et al. 2019

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Background: Betulinic acid is a pentacyclic lupane-type triterpenoid and a potential antiviral and antitumor drug, but the amount of betulinic acid in plants is low and cannot meet the demand for this compound. Yarrowia lipolytica, as an oleaginous yeast, is a promising microbial cell factory for the production of highly hydrophobic compounds due to the ability of this organism to accumulate large amounts of lipids that can store hydrophobic products and supply sufficient precursors for terpene synthesis. However, engineering for the heterologous production of betulinic acid and related triterpenoids has not developed as systematically as that for the production of other terpenoids, thus the production of betulinic acid in microbes remains unsatisfactory. Results: In this study, we applied a multimodular strategy to systematically improve the biosynthesis of betulinic acid and related triterpenoids in Y. lipolytica by engineering four functional modules, namely, the heterogenous CYP/CPR, MVA, acetyl-CoA generation, and redox cofactor supply modules. First, by screening 25 combinations of cytochrome P450 monooxygenases (CYPs) and NADPH-cytochrome P450 reductases (CPRs), each of which originated from 5 different sources, we selected two optimal betulinic acid-producing strains. Then, ERG1, ERG9, and HMG1 in the MVA module were overexpressed in the two strains, which dramatically increased betulinic acid production and resulted in a strain (YLJCC56) that exhibited the highest betulinic acid yield of 51.87 ± 2.77 mg/L. Then, we engineered the redox cofactor supply module by introducing NADPH-or NADH-generating enzymes and the acetyl-CoA generation module by directly overexpressing acetyl-CoA synthases or reinforcing the β-oxidation pathway, which further increased the total triterpenoid yield (the sum of the betulin, betulinic acid, betulinic aldehyde yields). Finally, we engineered these modules in combination, and the total triterpenoid yield reached 204.89 ± 11.56 mg/L (composed of 65.44% betulin, 23.71% betulinic acid and 10.85% betulinic aldehyde) in shake flask cultures. Conclusions: Here, we systematically engineered Y. lipolytica and achieved, to the best of our knowledge, the highest betulinic acid and total triterpenoid yields reported in microbes. Our study provides a suitable reference for studies on heterologous exploitation of P450 enzymes and manipulation of triterpenoid production in Y. lipolytica.

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Section: Introductionmentioning

confidence: 99%

Boosting the biosynthesis of betulinic acid and related triterpenoids in Yarrowia lipolytica via multimodular metabolic engineering

et al. 2019

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“…Recent expansion in the quantum information arriving as a result of tremendous evidence from the genome, transcriptome and proteome of several crops together with many aromatic and medicinal plants still needs many efforts to sharpening the tools more user-friendly for bioengineering. Though, there are still many challenges for assimilating the heterologous path in frame's cells for huge production resolution due to its limited categorized portions, module's unsuitability, and cell acceptance toward product [130]. The bioengineered tools are advanced sophisticated tools for pharmaceuticals and other industry where it can be attained more authentic evidence for better diversities in horticulture, postharvest value, improved nutritional value, improved resistant variations, and high-value pharmaceutical compounds.…”

Section: Perspective Future Outlook and Challenges Of Bioengineered mentioning

confidence: 99%

Bioengineering tools for the production of pharmaceuticals: current perspective and future outlook

2019

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The bioengineering tools have significant advantages through less time-consuming and utilized as a promising stage for the production of pharmaceutical bioproducts under the single platform. This review highlighted the advantages and current improvement in the plant, animal and microbial bioengineering tools and outlines feasible approaches by biological and process's bioengineering levels for advancing the economic feasibility of pharmaceutical's production. The critical analysis results revealed that system biology and synthetic biology along with advanced bioengineering tools like transcriptome, proteome, metabolome and nano bioengineering tools have shown a promising impact on the development of pharmaceutical's bioproducts. Tools to overcome and resolve the accompanying encounters of pharmaceutical's production that include nano bioengineering tools are also discussed. As a summary and prospect, it also gives new insight into the challenges and possible breakthrough of the development of pharmaceutical's bioproducts through bioengineering tools.

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“…So far nine projects have been supported with one related to plant and one to mammalian cells, the rest on microbial technology. Natural products (NPs) have always been an important area for synthetic biology research [4]. reviewed the progresses in discovery of novel biological parts and rational design of synthetic biological pathways, as well as pathway optimization [6].…”

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confidence: 99%

Synthetic biology in China, UK and US

2016

Synthetic and Systems Biotechnology

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Synbiological systems for complex natural products biosynthesis

Cited by 4 publications

References 73 publications

Boosting the biosynthesis of betulinic acid and related triterpenoids in Yarrowia lipolytica via multimodular metabolic engineering

Boosting the biosynthesis of betulinic acid and related triterpenoids in Yarrowia lipolytica via multimodular metabolic engineering

Bioengineering tools for the production of pharmaceuticals: current perspective and future outlook

Synthetic biology in China, UK and US

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