Engineering microbial fatty acid metabolism for biofuels and biochemicals

Marella, Eko Roy; Holkenbrink, Carina; Siewers, Verena; Borodina, Irina

doi:10.1016/j.copbio.2017.10.002

Cited by 124 publications

(91 citation statements)

References 49 publications

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“…Genetic studies of R. toruloides have shown that its lipid accumulation capacity can be further enhanced (reviewed in (Marella, Holkenbrink, Siewers, & Borodina, 2018)). We employed Flux Scanning based on Enforced Objective Function (FSEOF) on rhto-GEM to identify potential metabolic engineering targets for improved production of TAG.…”

Section: Prediction Of Potential Targets For Increased Production Of mentioning

confidence: 99%

Genome-scale model of Rhodotorula toruloides metabolism

Tiukova

Prigent

Nielsen

et al. 2019

Preprint

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10The basidiomycete red yeast Rhodotorula toruloides is a promising platform organism for production of biooils. We present rhto-GEM, the first genome-scale model (GEM) of R. toruloides metabolism, that was largely reconstructed using RAVEN toolbox. The model includes 926 genes, 4930 reactions, and 3374 metabolites, while lipid metabolism is described using the SLIMEr formalism allowing direct integration of lipid class and acyl chain experimental distribution data. The simulation results confirmed 15 that the R. toruloides model provides valid growth predictions on glucose, xylose and glycerol, while prediction of genetic engineering targets to increase production of linolenic acid, triacylglycerols and carotenoids highlighted genes that have previously been successfully used to increase production. This renders rtho-GEM valuable for future studies to improve the production of other oleochemicals of industrial relevance including value-added fatty acids and carotenoids, in addition to facilitate system-20 wide omics-data analysis in R. toruloides. Expanding the portfolio of GEMs for lipid accumulating fungi contributes to both understanding of metabolic mechanisms of the oleaginous phenotype but also uncover particularities of the lipid production machinery in R. toruloides.

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Section: Prediction Of Potential Targets For Increased Production Of mentioning

confidence: 99%

Genome-scale model of Rhodotorula toruloides metabolism

Tiukova

Prigent

Nielsen

et al. 2019

Preprint

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“…In this sense, central carbon metabolism, cofactor balance, regulation, and metabolite transport should be optimized. Current strategies to improve lipid production include increasing the supply of lipid precursors and/or avoiding lipid degradation together with the overcoming of limiting factors(Marella, Holkenbrink, Siewers, & Borodina, 2018; González-Fernández and Muñoz, 2017).…”

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confidence: 99%

Volatile fatty acids as novel building blocks for oil‐based chemistry via oleaginous yeast fermentation

Llamas

Magdalena

González‐Fernández

et al. 2019

Biotech & Bioengineering

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Microbial oils are proposed as a suitable alternative to petroleum‐based chemistry in terms of environmental preservation. These oils have traditionally been studied using sugar‐based feedstock, which implies high costs, substrate limitation, and high contamination risks. In this sense, low‐cost carbon sources such as volatile fatty acids (VFAs) are envisaged as promising building blocks for lipid biosynthesis to produce oil‐based bioproducts. VFAs can be generated from a wide variety of organic wastes through anaerobic digestion and further converted into lipids by oleaginous yeasts (OYs) in a fermentation process. These microorganisms can accumulate in the form of lipid bodies, lipids of up to 60% wt/wt of their biomass. In this context, OY is a promising biotechnological tool for biofuel and bioproduct generation using low‐cost VFA media as substrates. This review covers recent advances in microbial oil production from VFAs. Production of VFAs via anaerobic digestion processes and the involved metabolic pathways are reviewed. The main challenges as well as recent approaches for lipid overproduction are also discussed.

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“…[1][2][3] Ac lear structural understanding of ACPs and their interactions with partner enzymes is essential to furthering metabolic engineering and drug discovery.E fforts in this regard have proven challenging due to transient interactions and the dynamic nature of the ACP, which transports intermediates to multiple enzymes via ac ovalent but labile thioester linkage.T he archetypical carrier protein AcpP,w hich is involved in type II fatty acid biosynthesis in Escherichia coli,h as been well studied, [4,5] but key questions regarding conformational dynamics and interactions between AcpP and partner enzymes remain partially understood. We explored the importance of the thioester bond to the structure of the carrier protein by using solution NMR spectroscopya nd molecular dynamics simulations.Remarkably,the replacement of sulfur with other heteroatoms results in significant structural changes,t hus suggesting more rigorous selections of isosteric substitutes is needed.…”

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confidence: 99%

“…[1][2][3] Ac lear structural understanding of ACPs and their interactions with partner enzymes is essential to furthering metabolic engineering and drug discovery.E fforts in this regard have proven challenging due to transient interactions and the dynamic nature of the ACP, which transports intermediates to multiple enzymes via ac ovalent but labile thioester linkage.T he archetypical carrier protein AcpP,w hich is involved in type II fatty acid biosynthesis in Escherichia coli,h as been well studied, [4,5] but key questions regarding conformational dynamics and interactions between AcpP and partner enzymes remain partially understood. [1][2][3] Ac lear structural understanding of ACPs and their interactions with partner enzymes is essential to furthering metabolic engineering and drug discovery.E fforts in this regard have proven challenging due to transient interactions and the dynamic nature of the ACP, which transports intermediates to multiple enzymes via ac ovalent but labile thioester linkage.T he archetypical carrier protein AcpP,w hich is involved in type II fatty acid biosynthesis in Escherichia coli,h as been well studied, [4,5] but key questions regarding conformational dynamics and interactions between AcpP and partner enzymes remain partially understood.…”

mentioning

confidence: 99%

“…We explored the importance of the thioester bond to the structure of the carrier protein by using solution NMR spectroscopya nd molecular dynamics simulations.Remarkably,the replacement of sulfur with other heteroatoms results in significant structural changes,t hus suggesting more rigorous selections of isosteric substitutes is needed.Acyl carrier proteins (ACPs) are involved in pathways with metabolic,p harmaceutical, and environmental significance. [1][2][3] Ac lear structural understanding of ACPs and their interactions with partner enzymes is essential to furthering metabolic engineering and drug discovery.E fforts in this regard have proven challenging due to transient interactions and the dynamic nature of the ACP, which transports intermediates to multiple enzymes via ac ovalent but labile thioester linkage.T he archetypical carrier protein AcpP,w hich is involved in type II fatty acid biosynthesis in Escherichia coli,h as been well studied, [4,5] but key questions regarding conformational dynamics and interactions between AcpP and partner enzymes remain partially understood. Methods to capture ACP-partner proteins interactions have been developed, and often require the preparation of acyl-ACPs in which the naturally occurring thioester linkage has been replaced with am ore stable amide or ester bond.…”

mentioning

confidence: 99%

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Modifying the Thioester Linkage Affects the Structure of the Acyl Carrier Protein

Sztain

Patel

et al. 2019

Angewandte Chemie

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At the center of many complex biosynthetic pathways,t he acyl carrier protein (ACP) shuttles substrates to appropriate enzymatic partners to produce fatty acids and polyketides.C arrier proteins covalently tether their cargo via at hioester linkage to ap hosphopantetheine cofactor.D ue to the labile nature of this linkage,chemoenzymatic methods have been developed that involve replacement of the thioester with amore stable amide or ester bond. We explored the importance of the thioester bond to the structure of the carrier protein by using solution NMR spectroscopya nd molecular dynamics simulations.Remarkably,the replacement of sulfur with other heteroatoms results in significant structural changes,t hus suggesting more rigorous selections of isosteric substitutes is needed.Acyl carrier proteins (ACPs) are involved in pathways with metabolic,p harmaceutical, and environmental significance. [1][2][3] Ac lear structural understanding of ACPs and their interactions with partner enzymes is essential to furthering metabolic engineering and drug discovery.E fforts in this regard have proven challenging due to transient interactions and the dynamic nature of the ACP, which transports intermediates to multiple enzymes via ac ovalent but labile thioester linkage.T he archetypical carrier protein AcpP,w hich is involved in type II fatty acid biosynthesis in Escherichia coli,h as been well studied, [4,5] but key questions regarding conformational dynamics and interactions between AcpP and partner enzymes remain partially understood. Methods to capture ACP-partner proteins interactions have been developed, and often require the preparation of acyl-ACPs in which the naturally occurring thioester linkage has been replaced with am ore stable amide or ester bond. Chemoenzymatic preparations of ACPs bearing crosslinking probes have been used to covalently trap ACP-enzyme complexes. [6][7][8] Using this strategy,crystal structures of E. coli fatty acid ACP( AcpP) crosslinked to FabA, [9] FabB, [10] and FabZ [11] have been determined, which reveal discrete molec-ular interactions that mediate AcpP binding to these enzymes. What remains unknown, however, are the dynamics of these interactions throughout ACP-partner protein binding events, including how intermediates attached to the ACPi nfluence protein dynamics and molecular recognition. E. coli AcpP interacts with at least 25 different proteins [9,12,13] and transports acyl intermediates with chain lengths ranging from four to eighteen carbons that assume one of four different boxidation states.G iven the number of proteins with which AcpP interacts and the chemical diversity of the substrates it carries,itislikely that the process by which AcpP delivers its cargo (chain flipping) is not stochastic but rather regulated by substrate-influenced protein-protein interactions. [14] Due the geometric and electronic differences between thioester, ester,a nd amide linkages,e valuation of such modifications is necessary.W es ought to determine how the structure of AcpP is affected by the ...

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Engineering microbial fatty acid metabolism for biofuels and biochemicals

Cited by 124 publications

References 49 publications

Genome-scale model of Rhodotorula toruloides metabolism

Genome-scale model of Rhodotorula toruloides metabolism

Volatile fatty acids as novel building blocks for oil‐based chemistry via oleaginous yeast fermentation

Modifying the Thioester Linkage Affects the Structure of the Acyl Carrier Protein

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