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Title: Revisiting metabolic engineering strategies for microbial synthesis of oleochemicals

Journal Article · · Metabolic Engineering
 [1];  [2]
  1. Univ. of Wisconsin, Madison, WI (United States). Dept. of Chemical and Biological Engineering, and DOE Center for Advanced Bioenergy and Bioproducts Innovation; CABBI
  2. Univ. of Wisconsin, Madison, WI (United States). Dept. of Chemical and Biological Engineering, DOE Center for Advanced Bioenergy and Bioproducts Innovation, and Microbiology Doctoral Training Program

Microbial production of oleochemicals from renewable feedstocks remains an attractive route to produce high-energy density, liquid transportation fuels and high-value chemical products. Metabolic engineering strategies have been applied to demonstrate production of a wide range of oleochemicals, including free fatty acids, fatty alcohols, esters, olefins, alkanes, ketones, and polyesters in both bacteria and yeast. The majority of these demonstrations synthesized products containing long-chain fatty acids. These successes motivated additional effort to produce analogous molecules comprised of medium-chain fatty acids, molecules that are less common in natural oils and therefore of higher commercial value. Substantial progress has been made towards producing a subset of these chemicals, but significant work remains for most. The other primary challenge to producing oleochemicals in microbes is improving the performance, in terms of yield, rate, and titer, of biocatalysts such that economic large-scale processes are feasible. Common metabolic engineering strategies include blocking pathways that compete with synthesis of oleochemical building blocks and/or consume products, pulling flux through pathways by removing regulatory signals, pushing flux into biosynthesis by overexpressing rate-limiting enzymes, and engineering cells to tolerate the presence of oleochemical products. In this review, we describe the basic fundamentals of oleochemical synthesis and summarize advances since 2013 towards improving performance of heterotrophic microbial cell factories.

Research Organization:
Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), Urbana, IL (United States); Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Organization:
National Science Foundation (NSF); USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Grant/Contract Number:
SC0018420
OSTI ID:
1509679
Journal Information:
Metabolic Engineering, Journal Name: Metabolic Engineering Vol. 58; ISSN 1096-7176
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (144)

Brassica carinata - a new molecular farming platform for delivering bio-industrial oil feedstocks: case studies of genetic modifications to improve very long-chain fatty acid and oil content in seeds journal August 2010
A process for microbial hydrocarbon synthesis: Overproduction of fatty acids in Escherichia coli and catalytic conversion to alkanes journal June 2010
Systems metabolic engineering design: Fatty acid production as an emerging case study: Systems Metabolic Engineering Design journal February 2014
Functional replacement of the Saccharomyces cerevisiae fatty acid synthase with a bacterial type II system allows flexible product profiles : Functional Replacement of the journal September 2015
Engineering oxidative stress defense pathways to build a robust lipid production platform in Yarrowia lipolytica: Engineering robust microbial oil cell factory journal April 2017
Selective production of decanoic acid from iterative reversal of β-oxidation pathway journal February 2018
Improving methyl ketone production in Escherichia coli by heterologous expression of NADH-dependent FabG journal March 2018
Rational design of thiolase substrate specificity for metabolic engineering applications journal June 2018
Production of Propane and Other Short-Chain Alkanes by Structure-Based Engineering of Ligand Specificity in Aldehyde-Deformylating Oxygenase journal June 2013
Use of branched-chain esters to reduce the crystallization temperature of biodiesel journal October 1995
Structural determination and uses of jojoba oil journal February 1984
Synthesis and production of unsaturated and polyunsaturated fatty acids in yeast: current state and perspectives journal May 2012
Altering small and medium alcohol selectivity in the wax ester synthase journal July 2015
Synthesis of medium-chain length (C6–C10) fuels and chemicals via β-oxidation reversal in Escherichia coli journal February 2015
Biobased production of alkanes and alkenes through metabolic engineering of microorganisms journal August 2016
Microbial production of fatty alcohols journal July 2016
Biotechnological production of bio-based long-chain dicarboxylic acids with oleogenious yeasts journal October 2017
Structural insights into the catalytic mechanism of aldehyde-deformylating oxygenases journal December 2014
Potential uses of jojoba oil and meal — a review journal October 1994
Crystal Structure of Escherichia coli Thioesterase I/Protease I/Lysophospholipase L1: Consensus Sequence Blocks Constitute the Catalytic Center of SGNH-hydrolases through a Conserved Hydrogen Bond Network journal July 2003
Introduction of an acetyl-CoA carboxylation bypass into Escherichia coli for enhanced free fatty acid production journal December 2017
Synthetic biology for microbial production of lipid-based biofuels journal December 2015
Enzymes for fatty acid-based hydrocarbon biosynthesis journal December 2016
The Crystal Structure of Yeast Fatty Acid Synthase, a Cellular Machine with Eight Active Sites Working Together journal April 2007
Reprogramming Yeast Metabolism from Alcoholic Fermentation to Lipogenesis journal September 2018
Synthetic biology strategies for synthesizing polyhydroxyalkanoates from unrelated carbon sources journal November 2013
Acetyl Coenzyme A: A Central Metabolite and Second Messenger journal June 2015
Microbial production of fatty acid-derived fuels and chemicals journal December 2013
Engineering microbial fatty acid metabolism for biofuels and biochemicals journal April 2018
Steps towards ‘drop-in’ biofuels: focusing on metabolic pathways journal October 2018
A prokaryotic acyl-CoA reductase performing reduction of fatty acyl-CoA to fatty alcohol journal October 2011
Hot-melt coating with lipid excipients journal December 2013
Evaluation of biodiesels from several oilseed sources as environmental friendly contact herbicides journal June 2007
Heterologous production of pentane in the oleaginous yeast Yarrowia lipolytica journal June 2013
Adding value to plant oils and fatty acids: Biological transformation of fatty acids into ω-hydroxycarboxylic, α,ω-dicarboxylic, and ω-aminocarboxylic acids journal December 2015
Microbial production of 1-octanol: A naturally excreted biofuel with diesel-like properties journal December 2015
Engineering Escherichia coli to synthesize free fatty acids journal December 2012
Edible oils from microalgae: insights in TAG accumulation journal October 2014
Can We Approach Theoretical Lipid Yields in Microalgae? journal March 2018
Overproduction of free fatty acids in E. coli: Implications for biodiesel production journal November 2008
Engineering Escherichia coli for production of C12–C14 polyhydroxyalkanoate from glucose journal November 2012
An integrated computational and experimental study for overproducing fatty acids in Escherichia coli journal November 2012
Enhancing fatty acid production by the expression of the regulatory transcription factor FadR journal November 2012
Metabolic engineering of Saccharomyces cerevisiae for production of fatty acid-derived biofuels and chemicals journal January 2014
Production of medium chain length fatty alcohols from glucose in Escherichia coli journal November 2013
The initiation ketosynthase (FabH) is the sole rate-limiting enzyme of the fatty acid synthase of Synechococcus sp. PCC 7002 journal March 2014
Substantial improvements in methyl ketone production in E. coli and insights on the pathway from in vitro studies journal November 2014
Microbial acetyl-CoA metabolism and metabolic engineering journal March 2015
Engineering an iterative polyketide pathway in Escherichia coli results in single-form alkene and alkane overproduction journal March 2015
Metabolic engineering strategies for microbial synthesis of oleochemicals journal May 2015
Engineering lipid overproduction in the oleaginous yeast Yarrowia lipolytica journal May 2015
The oxidative pentose phosphate pathway is the primary source of NADPH for lipid overproduction from glucose in Yarrowia lipolytica journal July 2015
Rational design of a synthetic Entner–Doudoroff pathway for improved and controllable NADPH regeneration journal May 2015
Biosynthesis of odd-chain fatty alcohols in Escherichia coli journal May 2015
Evolution for exogenous octanoic acid tolerance improves carboxylic acid production and membrane integrity journal May 2015
Development of an orthogonal fatty acid biosynthesis system in E. coli for oleochemical production journal July 2015
Combinatorial metabolic engineering of Saccharomyces cerevisiae for terminal alkene production journal September 2015
Surveying the lipogenesis landscape in Yarrowia lipolytica through understanding the function of a Mga2p regulatory protein mutant journal September 2015
Modular and selective biosynthesis of gasoline-range alkanes journal January 2016
Combining metabolic engineering and process optimization to improve production and secretion of fatty acids journal November 2016
Engineering Escherichia coli to produce branched-chain fatty acids in high percentages journal November 2016
A systematic optimization of medium chain fatty acid biosynthesis via the reverse beta-oxidation cycle in Escherichia coli journal May 2017
Reversal of β-oxidative pathways for the microbial production of chemicals and polymer building blocks journal July 2017
Engineering high-level production of fatty alcohols by Saccharomyces cerevisiae from lignocellulosic feedstocks journal July 2017
Enabling the synthesis of medium chain alkanes and 1-alkenes in yeast journal November 2017
Design and application of genetically-encoded malonyl-CoA biosensors for metabolic engineering of microbial cell factories journal November 2017
Improving metabolic efficiency of the reverse beta-oxidation cycle by balancing redox cofactor requirement journal November 2017
Combination of type II fatty acid biosynthesis enzymes and thiolases supports a functional β-oxidation reversal journal January 2018
Heterologous transporter expression for improved fatty alcohol secretion in yeast journal January 2018
Model-assisted metabolic engineering of Escherichia coli for long chain alkane and alcohol production journal March 2018
Anaerobic production of medium-chain fatty alcohols via a β-reduction pathway journal July 2018
Engineering β-oxidation in Yarrowia lipolytica for methyl ketone production journal July 2018
Discovery of a Family of Desaturase-Like Enzymes for 1-Alkene Biosynthesis journal November 2015
Computational Redesign of Acyl-ACP Thioesterase with Improved Selectivity toward Medium-Chain-Length Fatty Acids journal May 2017
Analysis of Interdependent Kinetic Controls of Fatty Acid Synthases journal October 2018
Production of Medium Chain Fatty Acids by Yarrowia lipolytica: Combining Molecular Design and TALEN to Engineer the Fatty Acid Synthase journal June 2017
Matching Protein Interfaces for Improved Medium-Chain Fatty Acid Production journal April 2018
Highly Active C 8 -Acyl-ACP Thioesterase Variant Isolated by a Synthetic Selection Strategy journal July 2018
Biosynthesis of hydrocarbons in Anabaena variabilis. Incorporation of [methyl- 14 C] and [methyl- 2 H 2 ] Methionine into 7- and 8-methyl-heptadecanes journal January 1970
Characterization of a Fatty Acyl-CoA Reductase from Marinobacter aquaeolei VT8: A Bacterial Enzyme Catalyzing the Reduction of Fatty Acyl-CoA to Fatty Alcohol journal December 2011
Metabolic Flux between Unsaturated and Saturated Fatty Acids Is Controlled by the FabA:FabB Ratio in the Fully Reconstituted Fatty Acid Biosynthetic Pathway of Escherichia coli journal November 2013
Insights into Substrate and Metal Binding from the Crystal Structure of Cyanobacterial Aldehyde Deformylating Oxygenase with Substrate Bound journal September 2014
Rapid Reduction of the Diferric-Peroxyhemiacetal Intermediate in Aldehyde-Deformylating Oxygenase by a Cyanobacterial Ferredoxin: Evidence for a Free-Radical Mechanism journal September 2015
Reversal of the β-Oxidation Cycle in Saccharomyces cerevisiae for Production of Fuels and Chemicals journal June 2014
Microbial production of fatty-acid-derived fuels and chemicals from plant biomass journal January 2010
Engineered reversal of the β-oxidation cycle for the synthesis of fuels and chemicals journal August 2011
Microbial production of short-chain alkanes journal September 2013
Trapping the dynamic acyl carrier protein in fatty acid biosynthesis journal December 2013
Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids journal March 2012
Lipid production in Yarrowia lipolytica is maximized by engineering cytosolic redox metabolism journal January 2017
Microbial synthesis of medium-chain chemicals from renewables journal December 2017
Expanding the product portfolio of fungal type I fatty acid synthases journal February 2017
Production of fatty acid-derived oleochemicals and biofuels by synthetic yeast cell factories journal May 2016
Engineering fungal de novo fatty acid synthesis for short chain fatty acid production journal March 2017
Metabolic engineering of Saccharomyces cerevisiae for production of very long chain fatty acid-derived chemicals journal May 2017
Global rewiring of cellular metabolism renders Saccharomyces cerevisiae Crabtree negative journal August 2018
Barriers and opportunities in bio-based production of hydrocarbons journal July 2018
Diverse hydrocarbon biosynthetic enzymes can substitute for olefin synthase in the cyanobacterium Synechococcus sp. PCC 7002 journal February 2019
Cyanobacterial Alkanes Modulate Photosynthetic Cyclic Electron Flow to Assist Growth under Cold Stress journal October 2015
Production of FAME biodiesel in E. coli by direct methylation with an insect enzyme journal April 2016
Pathway Compartmentalization in Peroxisome of Saccharomyces cerevisiae to Produce Versatile Medium Chain Fatty Alcohols journal May 2016
Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering journal January 2015
The architectures of iterative type I PKS and FAS journal January 2018
Type II fatty acid and polyketide synthases: deciphering protein–protein and protein–substrate interactions journal January 2018
The Claisen condensation in biology journal July 2002
The chemical biology of modular biosynthetic enzymes journal January 2009
In vitro reconstitution and steady-state analysis of the fatty acid synthase from Escherichia coli journal October 2011
Controlled biosynthesis of odd-chain fuels and chemicals via engineered modular metabolic pathways journal October 2012
Carboxylic acid reductase is a versatile enzyme for the conversion of fatty acids into fuels and chemical commodities journal December 2012
Fusing catalase to an alkane-producing enzyme maintains enzymatic activity by converting the inhibitory byproduct H2O2 to the cosubstrate O2 journal February 2013
Tailored fatty acid synthesis via dynamic control of fatty acid elongation journal June 2013
Improving fatty acids production by engineering dynamic pathway regulation and metabolic control journal July 2014
Microbial biosynthesis of medium-chain 1-alkenes by a nonheme iron oxidase journal December 2014
Engineering Yarrowia lipolytica as a platform for synthesis of drop-in transportation fuels and oleochemicals journal September 2016
Repurposing type III polyketide synthase as a malonyl-CoA biosensor for metabolic engineering in bacteria journal September 2018
Enoyl-Acyl Carrier Protein Reductase ( fabI ) Plays a Determinant Role in Completing Cycles of Fatty Acid Elongation in Escherichia coli journal November 1995
Overproduction of Acetyl-CoA Carboxylase Activity Increases the Rate of Fatty Acid Biosynthesis in Escherichia coli journal July 2000
A Novel Bifunctional Wax Ester Synthase/Acyl-CoA:Diacylglycerol Acyltransferase Mediates Wax Ester and Triacylglycerol Biosynthesis in Acinetobacter calcoaceticus ADP1 journal December 2002
Ach1 is involved in shuttling mitochondrial acetyl units for cytosolic C2 provision in Saccharomyces cerevisiae lacking pyruvate decarboxylase journal April 2015
ThYme: a database for thioester-active enzymes journal November 2010
Microdiesel: Escherichia coli engineered for fuel production journal September 2006
Reconstitution of Plant Alkane Biosynthesis in Yeast Demonstrates That Arabidopsis ECERIFERUM1 and ECERIFERUM3 Are Core Components of a Very-Long-Chain Alkane Synthesis Complex journal July 2012
Microbial Biosynthesis of Alkanes journal July 2010
An Outlook on Microalgal Biofuels journal August 2010
Hydrocarbons of Blue-Green Algae: Geochemical Signfficance journal January 1969
Structure, Function, and Insights into the Biosynthesis of a Head-to-Head Hydrocarbon in Shewanella oneidensis Strain MR-1 journal April 2010
Modular Synthase-Encoding Gene Involved in α-Olefin Biosynthesis in Synechococcus sp. Strain PCC 7002 journal April 2011
Terminal Olefin (1-Alkene) Biosynthesis by a Novel P450 Fatty Acid Decarboxylase from Jeotgalicoccus Species journal January 2011
Driving Forces Enable High-Titer Anaerobic 1-Butanol Synthesis in Escherichia coli journal March 2011
Biochemical and Structural Studies of NADH-Dependent FabG Used To Increase the Bacterial Production of Fatty Acids under Anaerobic Conditions journal November 2013
Engineering Escherichia coli for Biodiesel Production Utilizing a Bacterial Fatty Acid Methyltransferase journal September 2011
Engineering of Bacterial Methyl Ketone Synthesis for Biofuels journal October 2011
Neutral Lipid Biosynthesis in Engineered Escherichia coli: Jojoba Oil-Like Wax Esters and Fatty Acid Butyl Esters journal February 2006
Inhibition of fatty acid synthesis in Escherichia coli in the absence of phospholipid synthesis and release of inhibition by thioesterase action. journal May 1994
Alteration of the specificity and regulation of fatty acid synthesis of Escherichia coli by expression of a plant medium-chain acyl-acyl carrier protein thioesterase. journal December 1994
beta -Ketoacyl-Acyl Carrier Protein Synthase III (FabH) Is a Determining Factor in Branched-Chain Fatty Acid Biosynthesis journal January 2000
The Acetate Switch journal March 2005
Improving Production of Malonyl Coenzyme A-Derived Metabolites by Abolishing Snf1-Dependent Regulation of Acc1 journal May 2014
Synthetic Biology for Engineering Acetyl Coenzyme A Metabolism in Yeast journal November 2014
Bacterial Membrane Lipids: Where Do We Stand? journal October 2003
An internal deletion in MTH1 enables growth on glucose of pyruvate-decarboxylase negative, non-fermentative Saccharomyces cerevisiae journal January 2012
Structure-oriented substrate specificity engineering of aldehyde-deformylating oxygenase towards aldehydes carbon chain length journal August 2016
Characterization of Cyanobacterial Hydrocarbon Composition and Distribution of Biosynthetic Pathways journal January 2014
Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions journal June 2015

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