Skip to main content
U.S. Department of Energy
Office of Scientific and Technical Information

Designing overall stoichiometric conversions and intervening metabolic reactions

Journal Article · · Scientific Reports
DOI:https://doi.org/10.1038/srep16009· OSTI ID:1242041
 [1];  [2]
  1. Pennsylvania State Univ., State College, PA (United States); Pennsylvania State University
  2. Pennsylvania State Univ., State College, PA (United States)
Existing computational tools for de novo metabolic pathway assembly, either based on mixed integer linear programming techniques or graph-search applications, generally only find linear pathways connecting the source to the target metabolite. The overall stoichiometry of conversion along with alternate co-reactant (or co-product) combinations is not part of the pathway design. Therefore, global carbon and energy efficiency is in essence fixed with no opportunities to identify more efficient routes for recycling carbon flux closer to the thermodynamic limit. Here, we introduce a two-stage computational procedure that both identifies the optimum overall stoichiometry (i.e., optStoic) and selects for (non-)native reactions (i.e., minRxn/minFlux) that maximize carbon, energy or price efficiency while satisfying thermodynamic feasibility requirements. Implementation for recent pathway design studies identified non-intuitive designs with improved efficiencies. Specifically, multiple alternatives for non-oxidative glycolysis are generated and non-intuitive ways of co-utilizing carbon dioxide with methanol are revealed for the production of C2+ metabolites with higher carbon efficiency.
Research Organization:
Pennsylvania State Univ., State College, PA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
SC0008091
OSTI ID:
1242041
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Vol. 5; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (114)

Bulk chemicals from biomass journal January 2008
Elementary flux modes in a nutshell: Properties, calculation and applications journal June 2013
Fully glycerol-independent microbial production of 1, 3-propanediol via non-natural pathway: Paving the way to success with synthetic tiles journal November 2014
Bio-based production of C2-C6 platform chemicals journal July 2012
Pyruvate Ferredoxin Oxidoreductase and Its Radical Intermediate journal August 2003
Beyond Oil and Gas: The Methanol Economy journal July 2005
Anaerobic oxidation of methane: an “active” microbial process journal December 2014
Calculation of Standard Transformed Formation Properties of Biochemical Reactants and Standard Apparent Reduction Potentials of Half Reactions journal October 1998
An Overview of Data Models for the Analysis of Biochemical Pathways book January 2003
Computational Tools for Guided Discovery and Engineering of Metabolic Pathways book January 2013
Biosynthesis of phloroglucinol compounds in microorganisms—review journal November 2011
Methane oxidation by anaerobic archaea for conversion to liquid fuels journal November 2014
Enhanced production of poly-3-hydroxybutyrate by Escherichia coli over-expressing multiple copies of NAD kinase integrated in the host genome journal February 2015
Regulation of the NADH and NADPH-ferredoxin oxidoreductases in Clostridia of the butyric group journal February 1976
Strategies for enhancing fermentative production of acetoin: A review journal March 2014
Recent advances in microbial production of fuels and chemicals using tools and strategies of systems metabolic engineering journal November 2015
Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression journal February 2021
Bilevel optimization techniques in computational strain design journal January 2015
Clostridia: the importance of their exceptional substrate and metabolite diversity for biofuel and biorefinery applications journal June 2012
Frontiers of yeast metabolic engineering: diversifying beyond ethanol and Saccharomyces journal December 2013
Computational approaches to metabolic engineering utilizing systems biology and synthetic biology journal August 2014
Dual synthetic pathway for 3-hydroxypropionic acid production in engineered Escherichia coli journal August 2015
Production of 3-hydroxypropionic acid via malonyl-CoA pathway using recombinant Escherichia coli strains journal February 2012
Synthesis, characterization, thermal and explosive properties of potassium salts of trinitrophloroglucinol journal August 2007
Metabolic engineering of Escherichia coli for 1-butanol production journal November 2008
Expanding the chemical palate of cells by combining systems biology and metabolic engineering journal July 2012
Mathematical optimization applications in metabolic networks journal November 2012
Novel approach to engineer strains for simultaneous sugar utilization journal November 2013
Model-driven rebalancing of the intracellular redox state for optimization of a heterologous n-butanol pathway in Escherichia coli journal November 2013
Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path journal September 2014
Recursive MILP model for finding all the alternate optima in LP models for metabolic networks journal July 2000
A Computational Approach To Design and Evaluate Enzymatic Reaction Pathways: Application to 1-Butanol Production from Pyruvate journal June 2011
Direct Mutagenesis of Thousands of Genomic Targets Using Microarray-Derived Oligonucleotides journal June 2014
Omic data from evolved E. coli are consistent with computed optimal growth from genome‐scale models journal January 2010
A genome‐scale metabolic reconstruction for Escherichia coli K‐12 MG1655 that accounts for 1260 ORFs and thermodynamic information journal January 2007
Engineered reversal of the β-oxidation cycle for the synthesis of fuels and chemicals journal August 2011
Anaerobic oxidation of methane coupled to nitrate reduction in a novel archaeal lineage journal July 2013
Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs journal January 2013
Rethinking biological activation of methane and conversion to liquid fuels journal April 2014
Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli journal June 2009
Recent advances in the heterologous expression of microbial natural product biosynthetic pathways journal January 2013
The unique features of glycolytic pathways in Archaea journal October 2003
The molecular toolbox for chromosomal heterologous multiprotein expression in Escherichia coli journal November 2012
Design and analysis of synthetic carbon fixation pathways journal April 2010
Improving fatty acids production by engineering dynamic pathway regulation and metabolic control journal July 2014
Building carbon–carbon bonds using a biocatalytic methanol condensation cycle journal October 2014
METATOOL: for studying metabolic networks journal March 1999
FluxAnalyzer: exploring structure, pathways, and flux distributions in metabolic networks on interactive flux maps journal January 2003
Exploring the diversity of complex metabolic networks journal December 2004
DESHARKY: automatic design of metabolic pathways for optimal cell growth journal September 2008
Exploring metabolic pathways in genome-scale networks via generating flux modes journal December 2010
Efficient searching and annotation of metabolic networks using chemical similarity journal December 2014
Synthesis of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) from unrelated carbon sources in engineered Rhodospirillum rubrum journal March 2015
FMM: a web server for metabolic pathway reconstruction and comparative analysis journal April 2009
Data, information, knowledge and principle: back to metabolism in KEGG journal November 2013
Metabolic tinker: an online tool for guiding the design of synthetic metabolic pathways journal April 2013
A New Route for Ethylene Glycol Metabolism in Mycobacterium E44 journal October 1980
Manufacturing Molecules Through Metabolic Engineering journal December 2010
Envisioning the Bioconversion of Methane to Liquid Fuels journal February 2014
Minimal Escherichia coli Cell for the Most Efficient Production of Ethanol from Hexoses and Pentoses journal April 2008
Novel Mode of Microbial Energy Metabolism: Organic Carbon Oxidation Coupled to Dissimilatory Reduction of Iron or Manganese journal January 1988
Comparative Analysis of Methane-Oxidizing Archaea and Sulfate-Reducing Bacteria in Anoxic Marine Sediments journal April 2001
Electron Bifurcation Involved in the Energy Metabolism of the Acetogenic Bacterium Moorella thermoacetica Growing on Glucose or H2 plus CO2 journal May 2012
MetRxn: a knowledgebase of metabolites and reactions spanning metabolic models and databases journal January 2012
A comparative analysis of the properties of regulated promoter systems commonly used for recombinant gene expression in Escherichia coli journal January 2013
Catabolic flexibility of mammalian-associated lactobacilli journal January 2013
k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design journal February 2014
Large-Scale Bi-Level Strain Design Approaches and Mixed-Integer Programming Solution Techniques journal September 2011
SEED Servers: High-Performance Access to the SEED Genomes, Annotations, and Metabolic Models journal October 2012
Phloroglucinol compounds of therapeutic interest: global patent and technology status journal April 2009
Minimal metabolic pathway structure is consistent with associated biomolecular interactions journal July 2014
Hypothetical glycerol pathways of newly isolated strains capable of 1,3-propanediol production. journal December 2014
Minimal cut sets in a metabolic network are elementary modes in a dual network text January 2012
Formate production through biocatalysis journal September 2013
Beyond Oil and Gas: The Methanol Economy journal April 2005
The Ribosome Binding Site Calculator book May 2011
Recursive MILP model for finding all the alternate optima in LP models for metabolic networks journal July 2000
MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development journal April 2015
Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression journal February 2013
A reverse glyoxylate shunt to build a non-native route from C4 to C2 in Escherichia coli journal September 2013
Establishing a synthetic pathway for high-level production of 3-hydroxypropionic acid in Saccharomyces cerevisiae via β-alanine journal January 2015
Heterogeneous Catalysts for the Guerbet Coupling of Alcohols journal June 2013
Pyruvate Ferredoxin Oxidoreductase and Its Radical Intermediate journal June 2003
ePathBrick: A Synthetic Biology Platform for Engineering Metabolic Pathways in E. coli journal May 2012
Biogeochemistry and microbial ecology of methane oxidation in anoxic environments: a review journal January 2002
Synthetic non-oxidative glycolysis enables complete carbon conservation journal September 2013
Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids journal March 2012
CRISPR-Cas systems for editing, regulating and targeting genomes journal March 2014
The unique features of glycolytic pathways in Archaea journal October 2003
The molecular toolbox for chromosomal heterologous multiprotein expression in Escherichia coli journal November 2012
Glycolytic strategy as a tradeoff between energy yield and protein cost journal April 2013
An overview of data models for the analysis of biochemical pathways journal January 2003
MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization journal July 2008
Pathway discovery in metabolic networks by subgraph extraction journal March 2010
Minimal cut sets in a metabolic network are elementary modes in a dual network journal December 2011
Random sampling of elementary flux modes in large-scale metabolic networks journal September 2012
FindPath: a Matlab solution for in silico design of synthetic metabolic pathways journal June 2014
XTMS: pathway design in an eXTended metabolic space journal May 2014
A vast collection of microbial genes that are toxic to bacteria journal February 2012
OptStrain: A computational framework for redesign of microbial production systems journal November 2004
Reconstruction of an Acetogenic 2,3-Butanediol Pathway Involving a Novel NADPH-Dependent Primary-Secondary Alcohol Dehydrogenase journal March 2014
2,3-Butanediol Production by Acetogenic Bacteria, an Alternative Route to Chemical Synthesis, Using Industrial Waste Gas journal June 2011
Platform Engineering of Corynebacterium glutamicum with Reduced Pyruvate Dehydrogenase Complex Activity for Improved Production of l-Lysine, l-Valine, and 2-Ketoisovalerate journal July 2013
Minimal Escherichia coli Cell for the Most Efficient Production of Ethanol from Hexoses and Pentoses journal April 2008
Hierarchy in Pentose Sugar Metabolism in Clostridium acetobutylicum journal December 2014
Novel Mode of Microbial Energy Metabolism: Organic Carbon Oxidation Coupled to Dissimilatory Reduction of Iron or Manganese journal January 1988
Comparative Analysis of Methane-Oxidizing Archaea and Sulfate-Reducing Bacteria in Anoxic Marine Sediments journal April 2001
Electron Bifurcation Involved in the Energy Metabolism of the Acetogenic Bacterium Moorella thermoacetica Growing on Glucose or H2 plus CO2 journal May 2012
Regulation of the Histidine Utilization (Hut) System in Bacteria journal August 2012
The Physiological Role of the Ribulose Monophosphate Pathway in Bacteria and Archaea journal January 2006
Efficient search, mapping, and optimization of multi-protein genetic systems in diverse bacteria journal June 2014
Developments in the Tools and Methodologies of Synthetic Biology journal November 2014
Succinate Overproduction: A Case Study of Computational Strain Design Using a Comprehensive Escherichia coli Kinetic Model journal January 2015
Metabolic Modelling in the Development of cell Factories by Synthetic Biology journal October 2012

Cited By (10)

A review of computational tools for design and reconstruction of metabolic pathways journal December 2017
Pathway design using de novo steps through uncharted biochemical spaces journal January 2018
Genome-Scale Metabolic Modeling of Archaea Lends Insight into Diversity of Metabolic Function journal January 2017
A review of parameters and heuristics for guiding metabolic pathfinding journal September 2017
A Prospective Study on the Fermentation Landscape of Gaseous Substrates to Biorenewables Using Methanosarcina acetivorans Metabolic Model journal August 2018
Holistic bioengineering: Rewiring central metabolism for enhanced bioproduction text January 2017
Expanding Metabolic Capabilities Using Novel Pathway Designs: Computational Tools and Case Studies journal July 2019
Pareto Optimality Explanation of the Glycolytic Alternatives in Nature journal February 2019
Holistic bioengineering: rewiring central metabolism for enhanced bioproduction journal November 2017
A metabolic reconstruction of Lactobacillus reuteri JCM 1112 and analysis of its potential as a cell factory journal October 2019

Similar Records

A review of computational tools for design and reconstruction of metabolic pathways
Journal Article · Tue Nov 14 19:00:00 EST 2017 · Synthetic and Systems Biotechnology · OSTI ID:1629793