Establishing a platform cell factory through engineering of yeast acetyl-CoA metabolism

Chen, Yun; Daviet, Laurent; Schalk, Michel; Siewers, Verena; Nielsen, Jens

doi:10.1016/j.ymben.2012.11.002

Cited by 275 publications

(229 citation statements)

References 26 publications

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“…The glyoxylate shunt could be disrupted by knocking out CIT2 or MLS1, which encodes peroxisomal citrate synthase and cytosolic malate synthase, respectively [7]. Compared with the reference strain with an intact glyoxylate shunt, the inactivation of CIT2 or MLS1 increased the production of α-santalene by 1.36-and 2.27-fold [6], 3-hydroxypropionic acid (3-HP) by 1.19-and 1.20-fold [75], and n-butanol by 1.58-and 1.36-fold [36], respectively. Interestingly, it was found that the production of polyhydroxybutyrate (PHB) was impaired in the ∆cit2 or ∆mls1 yeast strain [33].…”

Section: Inactivate Acetyl-coa Consuming Pathwaysmentioning

confidence: 99%

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Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites

Lian

Zhao

2015

Journal of Industrial Microbiology and Biotechnology

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Fatty acids or their activated forms, fatty acyl-CoAs and fatty acyl-ACPs, are important precursors to synthesize a wide variety of fuels and chemicals, including but not limited to free fatty acids (FFAs), fatty alcohols (FALs), fatty acid ethyl esters (FAEEs), and alkanes. However, Saccharomyces cerevisiae, an important cell factory, does not naturally accumulate fatty acids in large quantities. Therefore, metabolic engineering strategies were carried out to increase the glycolytic fluxes to fatty acid biosynthesis in yeast, specifically to enhance the supply of precursors, eliminate competing pathways, and bypass the host regulatory network. This review will focus on the genetic manipulation of both structural and regulatory genes in each step for fatty acids overproduction in S. cerevisiae, including from sugar to acetyl-CoA, from acetyl-CoA to malonyl-CoA, and from malonyl-CoA to fatty acyl-CoAs. The downstream pathways for the conversion of fatty acyl-CoAs to the desired products will also be discussed.

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Section: Inactivate Acetyl-coa Consuming Pathwaysmentioning

confidence: 99%

“…To overcome such limitations, a feedback inhibition insensitive ACS mutant from Salmonella enterica (SeAcs L641P ) [6,33,36,59] and/or alternative acetyl-CoA biosynthetic pathways with less energy input requirement (Fig. 3) were introduced to boost the availability of acetyl-CoA in yeast [34,67].…”

Section: Inactivate Acetyl-coa Consuming Pathwaysmentioning

confidence: 99%

Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites

Lian

Zhao

2015

Journal of Industrial Microbiology and Biotechnology

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“…ACS has been a target in multiple metabolic engineering strategies with S. cerevisiae for overproduction of acetyl-CoA-derived products (40)(41)(42), as well as for overproduction of NADPH for aerobic xylitol production (43). We chose to overexpress ACS2, which unlike ACS1 is not subject to glucose catabolite inactivation (44).…”

Section: Construction Of a Gpdmentioning

confidence: 99%

Increasing Anaerobic Acetate Consumption and Ethanol Yields in Saccharomyces cerevisiae with NADPH-Specific Alcohol Dehydrogenase

Henningsen

Hon

Covalla

et al. 2015

Appl Environ Microbiol

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Saccharomyces cerevisiae has recently been engineered to use acetate, a primary inhibitor in lignocellulosic hydrolysates, as a cosubstrate during anaerobic ethanolic fermentation. However, the original metabolic pathway devised to convert acetate to ethanol uses NADH-specific acetylating acetaldehyde dehydrogenase and alcohol dehydrogenase and quickly becomes constrained by limited NADH availability, even when glycerol formation is abolished. We present alcohol dehydrogenase as a novel target for anaerobic redox engineering of S. cerevisiae. Introduction of an NADPH-specific alcohol dehydrogenase (NADPH-ADH) not only reduces the NADH demand of the acetate-to-ethanol pathway but also allows the cell to effectively exchange NADPH for NADH during sugar fermentation. Unlike NADH, NADPH can be freely generated under anoxic conditions, via the oxidative pentose phosphate pathway. We show that an industrial bioethanol strain engineered with the original pathway (expressing acetylating acetaldehyde dehydrogenase from Bifidobacterium adolescentis and with deletions of glycerol-3-phosphate dehydrogenase genes GPD1 and GPD2) consumed 1.9 g liter ؊1 acetate during fermentation of 114 g liter ؊1 glucose. Combined with a decrease in glycerol production from 4.0 to 0.1 g liter ؊1 , this increased the ethanol yield by 4% over that for the wild type. We provide evidence that acetate consumption in this strain is indeed limited by NADH availability. By introducing an NADPH-ADH from Entamoeba histolytica and with overexpression of ACS2 and ZWF1, we increased acetate consumption to 5.3 g liter ؊1and raised the ethanol yield to 7% above the wild-type level. Saccharomyces cerevisiae is the principal microorganism used to produce ethanol, of which 93 billion liters were globally produced in 2014 (1). However, new strains are needed for the production of second-generation biofuels. Pretreatment and monomerization of lignocellulosic substrates produce complex sugar mixtures, including the C 5 sugars xylose and arabinose that are poorly fermented by most wild-type S. cerevisiae strains (2, 3). In addition, a variety of inhibitory compounds are released, such as furfural, hydroxymethylfurfural, methylglyoxal, and acetate (4-6). It is therefore desirable not only to expand the substrate range of S. cerevisiae (3, 7-9) but also to increase its inhibitor tolerance (10-13).Acetate is released during deacylation of hemicellulose and lignin and can be present in concentrations of Ͼ10 g liter Ϫ1 in cellulosic hydrolysates (4,14). At low pH particularly, this weak organic acid is a potent inhibitor of S. cerevisiae metabolism (15-17). Unfortunately, wild-type S. cerevisiae strains are poorly equipped to eliminate acetate from the medium under anoxic conditions. S. cerevisiae can grow on acetate as the sole carbon source under oxic conditions by converting acetate to acetyl coenzyme A (acetyl-CoA) with acetyl-CoA synthetase (ACS) (EC 6.2.1.1) and by either respiring acetyl-CoA in the tricarboxylic acid (TCA) cycle or upgrading acetyl-CoA to four-...

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“…They used S. cerevisiae as the host and genetic engineering strategies focused on enhancing the acetyl-CoA pool, precursors for the MVA pathway. Overexpression of the enzymes ald6 and Salmonella enterica acs1, adh2, and repression of ERG9, which encodes squalene synthase, and over expression of HMG1 were some of the strategies used to enhance farnesene yield (Shiba et al 2007;Ohto et al 2009;Asadollahi et al 2008;Asadollahi et al 2010;Chen et al 2012). The titer of farnesane obtained was ~14 g/L, which still far lower than what is obtained in industrial ethanol fermentation (Amyris 2013).…”

Section: Metabolic Engineering For Isoprenoid Productionmentioning

confidence: 98%

Can Microbially Derived Advanced Biofuels Ever Compete with Conventional Bioethanol? A Critical Review

Veettil

Kumar

Koukoulas³

2016

BioResources

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Establishing a platform cell factory through engineering of yeast acetyl-CoA metabolism

Cited by 275 publications

References 26 publications

Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites

Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites

Increasing Anaerobic Acetate Consumption and Ethanol Yields in Saccharomyces cerevisiae with NADPH-Specific Alcohol Dehydrogenase

Can Microbially Derived Advanced Biofuels Ever Compete with Conventional Bioethanol? A Critical Review

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