Increasing Malonyl-CoA Derived Product through Controlling the Transcription Regulators of Phospholipid Synthesis in <i>Saccharomyces cerevisiae</i>

Chen, Xiaoxu; Yang, Xiaoyu; Shen, Yu; Hou, Jin; Bao, Xinhe

doi:10.1021/acssynbio.6b00346

Cited by 30 publications

(22 citation statements)

References 31 publications

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“…Since Ino2 is an activator of many fatty acid and phospholipid biosynthesis genes, an increase in PA levels indirectly causes an up-regulation of the fatty acid biosynthesis machinery ( Fig. 3 B ) ( 23 – 25 ).…”

Section: Resultsmentioning

confidence: 99%

Redirection of lipid flux toward phospholipids in yeast increases fatty acid turnover and secretion

Ferreira

Teixeira

Siewers

et al. 2018

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

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SignificanceReplacement of nonrenewable petrochemicals and liquid fuels requires sustainable production of oleochemicals. Free fatty acids (FFAs) are versatile molecules that can be produced by microbial fermentation and are used as precursors for production of these oleochemicals. In the past few years, we have seen major advancements in improving the yeast Saccharomyces cerevisiae for FFA production. Despite these successes, lipid metabolism is highly complex, and the pathways and metabolites involved in the formation of FFAs in yeast remain incompletely understood. In this work, we make important advancements in understanding the dynamics of FFA formation in the cell and explore the role of phospholipids in this process.

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Section: Resultsmentioning

confidence: 99%

Redirection of lipid flux toward phospholipids in yeast increases fatty acid turnover and secretion

Ferreira

Teixeira

Siewers

et al. 2018

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

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“…In our previous study, overexpression of four key genes encoding AccA, AccB, AccC, and AccD was also able to improve the malonyl-CoA supply, eventually leading to an increased 3-HP production up to 4.5-fold [ 34 ]. In addition, by engineering phospholipid synthesis transcriptional regulators in S. cerevisiae , a significant increase of malonyl-CoA content in the engineered strains and ninefold increase of the titer of malonyl-CoA-derived 3-HP were achieved [ 47 ]. In this work, in accordance with the previous study using PTRNA tool to regulate the malonyl-CoA supply [ 18 ], we decreased the flux from both acetyl-CoA and malonyl-CoA to fatty acids biosynthesis using the Hfq-MicC tool to downregulating two ( slr1511 and slr2023 ) or four genes ( slr1511 , sll1069 , slr1332 and slr2023 ), leading to a significant increase of malonyl-CoA content in cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Re-direction of carbon flux to key precursor malonyl-CoA via artificial small RNAs in photosynthetic Synechocystis sp. PCC 6803

Sun

Song

et al. 2018

Biotechnol Biofuels

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BackgroundPhotosynthetic cyanobacteria have attracted a significant attention as promising chassis to produce renewable fuels and chemicals due to their capability to utilizing solar energy and CO2. Notably, the enhancing supply of key precursors like malonyl-CoA would benefit the production of many bio-compounds. Nevertheless, the lacking of genetic tools in cyanobacteria, especially the knockdown strategies for essential pathways, has seriously restricted the attempts to re-direct carbon flux from the central carbohydrate metabolism to the synthesis of bioproducts.ResultsAiming at developing new genetic tools, two small RNA regulatory tools are reported for the model cyanobacterium Synechocystis sp. PCC6803, based on paired termini RNAs as well as the exogenous Hfq chaperone and MicC scaffold (Hfq-MicC) previously developed in Escherichia coli. Both regulatory tools functioned well in regulating exogenous reporter gene lacZ and endogenous glgC gene in Synechocystis sp. PCC6803, achieving a downregulation of gene expression up to 90% compared with wildtype. In addition, the Hfq-MicC tool was developed to simultaneously regulate multiple genes related to essential fatty acids biosynthesis, which led to decreased fatty acids content by 11%. Furthermore, aiming to re-direct the carbon flux, the Hfq-MicC tool was utilized to interfere the competing pathway of malonyl-CoA, achieving an increased intracellular malonyl-CoA abundance up to 41% (~ 698.3 pg/mL/OD730 nm) compared to the wildtype. Finally, the Hfq-MicC system was further modified into an inducible system based on the theophylline-inducible riboswitch.ConclusionsIn this study, two small RNA regulatory tools for manipulating essential metabolic pathways and re-directing carbon flux are reported for Synechocystis sp. PCC6803. The work introduces efficient and valuable metabolic regulatory strategies for photosynthetic cyanobacteria.Electronic supplementary materialThe online version of this article (10.1186/s13068-018-1032-0) contains supplementary material, which is available to authorized users.

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“…Reducing the diversion of malonyl-CoA to essential pathways is a challenge, because fatty acids are required for biomass production. In yeast, knockout of genes regulating fatty acid biosynthesis improved titers of malonyl-CoA-derived products (Zha et al, 2009;Chen et al, 2017), yet the strain was auxotrophic for inositol. More promisingly, biomass accumulation prior to conditional gene knockdown has been demonstrated to improve polyketide titers in E. coli (Yang et al, 2015b(Yang et al, , 2018Liang et al, 2016;Wu et al, 2016a).…”

Section: Precursor Supplymentioning

confidence: 99%

Engineering Plant Secondary Metabolism in Microbial Systems

2019

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Secondary metabolites are broadly defined as natural products synthesized by an organism that are not essential to support growth and life. The plant kingdom manufactures over 200,000 distinct chemical compounds, most of which arise from specialized metabolism. While these compounds play important roles in interspecies competition and defense, many plant natural products have been exploited for use as medicines, fragrances, flavors, nutrients, repellants, and colorants. Despite this vast chemical diversity, many secondary metabolites are present at very low concentrations in planta, eliminating crop-based manufacturing as a means of attaining these important products. The structural and stereochemical complexity of specialized metabolites hinders most attempts to access these compounds using chemical synthesis. Although native plants can be engineered to accumulate target pathway metabolites (Zhou et al.

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Increasing Malonyl-CoA Derived Product through Controlling the Transcription Regulators of Phospholipid Synthesis in Saccharomyces cerevisiae

Cited by 30 publications

References 31 publications

Redirection of lipid flux toward phospholipids in yeast increases fatty acid turnover and secretion

Redirection of lipid flux toward phospholipids in yeast increases fatty acid turnover and secretion

Re-direction of carbon flux to key precursor malonyl-CoA via artificial small RNAs in photosynthetic Synechocystis sp. PCC 6803

Engineering Plant Secondary Metabolism in Microbial Systems

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