k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design

Chowdhury, Anupam; Zomorrodi, Ali R.; Maranas, Costas D.

doi:10.1371/journal.pcbi.1003487

Title: k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design

Abstract

Computational strain design protocols aim at the system-wide identification of intervention strategies for the enhanced production of biochemicals in microorganisms. Existing approaches relying solely on stoichiometry and rudimentary constraint-based regulation overlook the effects of metabolite concentrations and substrate-level enzyme regulation while identifying metabolic interventions. In this paper, we introduce k-OptForce, which integrates the available kinetic descriptions of metabolic steps with stoichiometric models to sharpen the prediction of intervention strategies for improving the bio-production of a chemical of interest. It enables identification of a minimal set of interventions comprised of both enzymatic parameter changes (for reactions with available kinetics) and reaction flux changes (for reactions with only stoichiometric information). Application of k-OptForce to the overproduction of L-serine in E. coli and triacetic acid lactone (TAL) in S. cerevisiae revealed that the identified interventions tend to cause less dramatic rearrangements of the flux distribution so as not to violate concentration bounds. In some cases the incorporation of kinetic information leads to the need for additional interventions as kinetic expressions render stoichiometry-only derived interventions infeasible by violating concentration bounds, whereas in other cases the kinetic expressions impart flux changes that favor the overproduction of the target product thereby requiring fewer direct interventions. Amore »« less

Authors:

Chowdhury, Anupam ^[1]; Zomorrodi, Ali R. ^[1]; Maranas, Costas D. ^[1]

Pennsylvania State Univ., University Park, PA (United States). Dept. of Chemical Engineering

Publication Date:: Thu Feb 20 00:00:00 EST 2014

Research Org.:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Org.:: USDOE; National Science Foundation (NSF)

OSTI Identifier:: 1903940

Grant/Contract Number:: SC10822882; EEC-0813570

Resource Type:: Accepted Manuscript

Journal Name:: PLoS Computational Biology (Online)

Additional Journal Information:: Journal Name: PLoS Computational Biology (Online); Journal Volume: 10; Journal Issue: 2; Journal ID: ISSN 1553-7358

Publisher:: Public Library of Science

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Mathematical & Computational Biology

Citation Formats


                    Chowdhury, Anupam, Zomorrodi, Ali R., and Maranas, Costas D. k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design.  United States: N. p., 2014. 
Web.  doi:10.1371/journal.pcbi.1003487.

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                    Chowdhury, Anupam, Zomorrodi, Ali R., & Maranas, Costas D. k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design.  United States.  https://doi.org/10.1371/journal.pcbi.1003487

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                    Chowdhury, Anupam, Zomorrodi, Ali R., and Maranas, Costas D. Thu .  
"k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design".  United States.  https://doi.org/10.1371/journal.pcbi.1003487.  https://www.osti.gov/servlets/purl/1903940.

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@article{osti_1903940,

  title        = {k-OptForce: Integrating Kinetics with Flux Balance Analysis for Strain Design},

  author       = {Chowdhury, Anupam and Zomorrodi, Ali R. and Maranas, Costas D.},

  abstractNote = {Computational strain design protocols aim at the system-wide identification of intervention strategies for the enhanced production of biochemicals in microorganisms. Existing approaches relying solely on stoichiometry and rudimentary constraint-based regulation overlook the effects of metabolite concentrations and substrate-level enzyme regulation while identifying metabolic interventions. In this paper, we introduce k-OptForce, which integrates the available kinetic descriptions of metabolic steps with stoichiometric models to sharpen the prediction of intervention strategies for improving the bio-production of a chemical of interest. It enables identification of a minimal set of interventions comprised of both enzymatic parameter changes (for reactions with available kinetics) and reaction flux changes (for reactions with only stoichiometric information). Application of k-OptForce to the overproduction of L-serine in E. coli and triacetic acid lactone (TAL) in S. cerevisiae revealed that the identified interventions tend to cause less dramatic rearrangements of the flux distribution so as not to violate concentration bounds. In some cases the incorporation of kinetic information leads to the need for additional interventions as kinetic expressions render stoichiometry-only derived interventions infeasible by violating concentration bounds, whereas in other cases the kinetic expressions impart flux changes that favor the overproduction of the target product thereby requiring fewer direct interventions. A sensitivity analysis on metabolite concentrations shows that the required number of interventions can be significantly affected by changing the imposed bounds on metabolite concentrations. Furthermore, k-OptForce was capable of finding non-intuitive interventions aiming at alleviating the substrate-level inhibition of key enzymes in order to enhance the flux towards the product of interest, which cannot be captured by stoichiometry-alone analysis. This study paves the way for the integrated analysis of kinetic and stoichiometric models and enables elucidating system-wide metabolic interventions while capturing regulatory and kinetic effects.},

  doi          = {10.1371/journal.pcbi.1003487},

  journal      = {PLoS Computational Biology (Online)},

  number       = 2,

  volume       = 10,

  place        = {United States},

  year         = {Thu Feb 20 00:00:00 EST 2014},

  month        = {Thu Feb 20 00:00:00 EST 2014}

}

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Large-scale kinetic models provide the computational means to dynamically link metabolic reaction fluxes to metabolite concentrations and enzyme levels while also conforming to substrate level regulation. However, the development of broadly applicable frameworks for efficiently and robustly parameterizing models remains a challenge. Challenges arise due to both the heterogeneity, paucity, and difficulty in obtaining flux and/or concentration data but also due to the computational difficulties of the underlying parameter identification problem. Both the computational demands for parameterization, degeneracy of obtained parameter solutions and interpretability of results has so far limited widespread adoption of large-scale kinetic models despite their potential. Herein,more »« less
https://doi.org/10.1016/j.ymben.2024.02.002
From Escherichia coli mutant ¹³C labeling data to a core kinetic model: A kinetic model parameterization pipeline

Journal Article Foster, Charles J. ; Gopalakrishnan, Saratram ; Antoniewicz, Maciek R. ; ... - PLoS Computational Biology (Online)

Kinetic models of metabolic networks offer the promise of quantitative phenotype prediction. The mechanistic characterization of enzyme catalyzed reactions allows for tracing the effect of perturbations in metabolite concentrations and reaction fluxes in response to genetic and environmental perturbation that are beyond the scope of stoichiometric models. In this study, we develop a two-step computational pipeline for the rapid parameterization of kinetic models of metabolic networks using a curated metabolic model and available ¹³C-labeling distributions under multiple genetic and environmental perturbations. The first step involves the elucidation of all intracellular fluxes in a core model of E. coli containing 74more »« less
https://doi.org/10.1371/journal.pcbi.1007319

Full Text Available
A review of computational tools for design and reconstruction of metabolic pathways

Journal Article Wang, Lin ; Dash, Satyakam ; Ng, Chiam Yu ; ... - Synthetic and Systems Biotechnology

Metabolic pathways reflect an organism's chemical repertoire and hence their elucidation and design have been a primary goal in metabolic engineering. Various computational methods have been developed to design novel metabolic pathways while taking into account several prerequisites such as pathway stoichiometry, thermodynamics, host compatibility, and enzyme availability. The choice of the method is often determined by the nature of the metabolites of interest and preferred host organism, along with computational complexity and availability of software tools. In this paper, we review different computational approaches used to design metabolic pathways based on the reaction network representation of the database (i.e.,more »« less
https://doi.org/10.1016/j.synbio.2017.11.002

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Abstract

Citation Formats

Challenges in lin-log modelling of glycolysis in Lactococcus lactis journal, January 2008

Optimization-driven identification of genetic perturbations accelerates the convergence of model parameters in ensemble modeling of metabolic networks journal, June 2013

Microbial synthesis of triacetic acid lactone journal, January 2006

On the Use of Metabolic Control Analysis in the Optimization of Cyanobacterial Biosolar Cell Factories journal, March 2013

Rational Pathway Engineering of Type I Fatty Acid Synthase Allows the Biosynthesis of Triacetic Acid Lactone from d -Glucose in Vivo journal, April 2004

Escherichia coli K-12 undergoes adaptive evolution to achieve in silico predicted optimal growth journal, November 2002

Prediction of dynamic behavior of mutant strains from limited wild-type data journal, March 2012

Towards a genome-scale kinetic model of cellular metabolism journal, January 2010

Modeling of uncertainties in biochemical reactions journal, October 2010

Metabolic Capabilities of Escherichia coli: I. Synthesis of Biosynthetic Precursors and Cofactors journal, December 1993

Pyruvate Metabolism inSaccharomyces cerevisiae journal, December 1996

Modeling and simulation of the main metabolism in Escherichia coli and its several single-gene knockout mutants with experimental verification journal, January 2010

EMILiO: A fast algorithm for genome-scale strain design journal, May 2011

Dynamic modelling and analysis of biochemical networks: mechanism-based models and model-based experiments journal, September 2006

Testing Biochemistry Revisited: How In Vivo Metabolism Can Be Understood from In Vitro Enzyme Kinetics journal, April 2012

Systems metabolic engineering of microorganisms for natural and non-natural chemicals journal, May 2012

Mathematical optimization applications in metabolic networks journal, November 2012

Dynamic modeling of the central carbon metabolism ofEscherichia coli journal, May 2002

Recent developments in parameter estimation and structure identification of biochemical and genomic systems journal, June 2009

Mass Action Stoichiometric Simulation Models: Incorporating Kinetics and Regulation into Stoichiometric Models journal, January 2010

Mass Action Stoichiometric Simulation Models: Incorporating Kinetics and Regulation into Stoichiometric Models journal, January 2010

Analysis of optimality in natural and perturbed metabolic networks journal, November 2002

Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data journal, December 2010

Ensemble Modeling for Aromatic Production in Escherichia coli journal, September 2009

Regulation of phosphoglycerate dehydrogenase levels and effect on serine synthesis in Escherichia coli K-12 journal, January 1980

OptStrain: A computational framework for redesign of microbial production systems journal, November 2004

Model-driven evaluation of the production potential for growth-coupled products of Escherichia coli journal, May 2010

Metabolic Engineering from a Cybernetic Perspective: Aspartate Family of Amino Acids journal, January 1999

Multiple High-Throughput Analyses Monitor the Response of E. coli to Perturbations journal, April 2007

Genome-scale dynamic modeling of the competition between Rhodoferax and Geobacter in anoxic subsurface environments journal, July 2010

Structural kinetic modeling of metabolic networks journal, July 2006

An optimization framework for identifying reaction activation/inhibition or elimination candidates for overproduction in microbial systems journal, January 2006

Parameter optimization and sensitivity analysis for large kinetic models using a real-coded genetic algorithm journal, April 2013

Optimal re-design of primary metabolism in Escherichia coli using linlog kinetics journal, October 2004

Rational Pathway Engineering of Type I Fatty Acid Synthase Allows the Biosynthesis of Triacetic Acid Lactone from d -Glucose in Vivo journal, April 2004

The effects of alternate optimal solutions in constraint-based genome-scale metabolic models journal, October 2003

In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data journal, February 2001

Microbial synthesis of triacetic acid lactone journal, January 2006

Cra and the control of carbon flux via metabolic pathways journal, July 1996

3-Phosphoglycerate dehydrogenase from Corynebacterium glutamicum : the C-terminal domain is not essential for activity but is required for inhibition by L -serine journal, December 2002

Challenges in lin-log modelling of glycolysis in Lactococcus lactis journal, January 2008

Kinetic modeling using S-systems and lin-log approaches journal, March 2007

Approximative kinetic formats used in metabolic network modeling journal, January 2005

Ensemble Modeling of Metabolic Networks journal, December 2008

Metabolic engineering and flux analysis of Corynebacterium glutamicum for L-serine production journal, April 2012

Towards systems metabolic engineering of microorganisms for amino acid production journal, October 2008

Dynamic modeling of the central carbon metabolism ofEscherichia coli journal, May 2002

Hybrid dynamic modeling of Escherichia coli central metabolic network combining Michaelis–Menten and approximate kinetic equations journal, May 2010

Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli journal, May 2005

Expanding the chemical palate of cells by combining systems biology and metabolic engineering journal, July 2012

In silico aided metabolic engineering of Saccharomyces cerevisiae for improved bioethanol production journal, November 2005

OptStrain: A computational framework for redesign of microbial production systems journal, November 2004

Enhancing sesquiterpene production in Saccharomyces cerevisiae through in silico driven metabolic engineering journal, November 2009

Systems metabolic engineering of microorganisms for natural and non-natural chemicals journal, May 2012

Modeling of uncertainties in biochemical reactions journal, October 2010

Metabolic Engineering from a Cybernetic Perspective. 1. Theoretical Preliminaries journal, June 1999

k-Cone Analysis: Determining All Candidate Values for Kinetic Parameters on a Network Scale journal, March 2005

Integrating metabolic, transcriptional regulatory and signal transduction models in Escherichia coli journal, July 2008

Integrated stoichiometric, thermodynamic and kinetic modelling of steady state metabolism journal, June 2010

An integrated computational environment for elementary modes analysis of biochemical networks journal, January 2012

Application of dynamic flux balance analysis to an industrial Escherichia coli fermentation journal, March 2010

Effect of lpdA gene knockout on the metabolism in Escherichia coli based on enzyme activities, intracellular metabolite concentrations and metabolic flux analysis by 13C-labeling experiments journal, March 2006

Structural kinetic modeling of metabolic networks journal, July 2006

Genome-scale dynamic modeling of the competition between Rhodoferax and Geobacter in anoxic subsurface environments journal, July 2010

Full-scale model of glycolysis in Saccharomyces cerevisiae journal, December 2001

Genome-scale metabolic network modeling results in minimal interventions that cooperatively force carbon flux towards malonyl-CoA journal, September 2011

Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids journal, March 2007

Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data journal, December 2010

Analysis of optimality in natural and perturbed metabolic networks journal, November 2002

Ensemble Modeling for Aromatic Production in Escherichia coli journal, September 2009

A genome‐scale metabolic reconstruction for Escherichia coli K‐12 MG1655 that accounts for 1260 ORFs and thermodynamic information journal, January 2007

Predicting metabolic engineering knockout strategies for chemical production: accounting for competing pathways journal, December 2009

Tolerance and Specificity of Recombinant 6-Methylsalicylic Acid Synthase journal, April 1999

Genome-scale models of bacterial metabolism: reconstruction and applications journal, January 2009

Dynamic Analysis of Integrated Signaling, Metabolic, and Regulatory Networks journal, May 2008

Metabolic Engineering from a Cybernetic Perspective: Aspartate Family of Amino Acids journal, January 1999

Deoxygenation of Polyhydroxybenzenes: An Alternative Strategy for the Benzene-Free Synthesis of Aromatic Chemicals journal, May 2002

Challenges in lin-log modelling of glycolysis in Lactococcus lactis
journal, January 2008

Optimization-driven identification of genetic perturbations accelerates the convergence of model parameters in ensemble modeling of metabolic networks
journal, June 2013

Microbial synthesis of triacetic acid lactone
journal, January 2006

On the Use of Metabolic Control Analysis in the Optimization of Cyanobacterial Biosolar Cell Factories
journal, March 2013

Rational Pathway Engineering of Type I Fatty Acid Synthase Allows the Biosynthesis of Triacetic Acid Lactone from d -Glucose in Vivo
journal, April 2004

Escherichia coli K-12 undergoes adaptive evolution to achieve in silico predicted optimal growth
journal, November 2002

Prediction of dynamic behavior of mutant strains from limited wild-type data
journal, March 2012

Towards a genome-scale kinetic model of cellular metabolism
journal, January 2010

Modeling of uncertainties in biochemical reactions
journal, October 2010

Metabolic Capabilities of Escherichia coli: I. Synthesis of Biosynthetic Precursors and Cofactors
journal, December 1993

Pyruvate Metabolism inSaccharomyces cerevisiae
journal, December 1996

Modeling and simulation of the main metabolism in Escherichia coli and its several single-gene knockout mutants with experimental verification
journal, January 2010

EMILiO: A fast algorithm for genome-scale strain design
journal, May 2011

Dynamic modelling and analysis of biochemical networks: mechanism-based models and model-based experiments
journal, September 2006

Testing Biochemistry Revisited: How In Vivo Metabolism Can Be Understood from In Vitro Enzyme Kinetics
journal, April 2012

Systems metabolic engineering of microorganisms for natural and non-natural chemicals
journal, May 2012

Mathematical optimization applications in metabolic networks
journal, November 2012

Dynamic modeling of the central carbon metabolism ofEscherichia coli
journal, May 2002

Recent developments in parameter estimation and structure identification of biochemical and genomic systems
journal, June 2009

Mass Action Stoichiometric Simulation Models: Incorporating Kinetics and Regulation into Stoichiometric Models
journal, January 2010

Mass Action Stoichiometric Simulation Models: Incorporating Kinetics and Regulation into Stoichiometric Models
journal, January 2010

Analysis of optimality in natural and perturbed metabolic networks
journal, November 2002

Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data
journal, December 2010

Ensemble Modeling for Aromatic Production in Escherichia coli
journal, September 2009

Regulation of phosphoglycerate dehydrogenase levels and effect on serine synthesis in Escherichia coli K-12
journal, January 1980

OptStrain: A computational framework for redesign of microbial production systems
journal, November 2004

Model-driven evaluation of the production potential for growth-coupled products of Escherichia coli
journal, May 2010

Metabolic Engineering from a Cybernetic Perspective: Aspartate Family of Amino Acids
journal, January 1999

Multiple High-Throughput Analyses Monitor the Response of E. coli to Perturbations
journal, April 2007

Genome-scale dynamic modeling of the competition between Rhodoferax and Geobacter in anoxic subsurface environments
journal, July 2010

Structural kinetic modeling of metabolic networks
journal, July 2006

An optimization framework for identifying reaction activation/inhibition or elimination candidates for overproduction in microbial systems
journal, January 2006

Parameter optimization and sensitivity analysis for large kinetic models using a real-coded genetic algorithm
journal, April 2013

Optimal re-design of primary metabolism in Escherichia coli using linlog kinetics
journal, October 2004

Rational Pathway Engineering of Type I Fatty Acid Synthase Allows the Biosynthesis of Triacetic Acid Lactone from d -Glucose in Vivo
journal, April 2004

The effects of alternate optimal solutions in constraint-based genome-scale metabolic models
journal, October 2003

In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data
journal, February 2001

Microbial synthesis of triacetic acid lactone
journal, January 2006

Cra and the control of carbon flux via metabolic pathways
journal, July 1996

3-Phosphoglycerate dehydrogenase from Corynebacterium glutamicum : the C-terminal domain is not essential for activity but is required for inhibition by L -serine
journal, December 2002

Challenges in lin-log modelling of glycolysis in Lactococcus lactis
journal, January 2008

Kinetic modeling using S-systems and lin-log approaches
journal, March 2007

Approximative kinetic formats used in metabolic network modeling
journal, January 2005

Ensemble Modeling of Metabolic Networks
journal, December 2008

Metabolic engineering and flux analysis of Corynebacterium glutamicum for L-serine production
journal, April 2012

Towards systems metabolic engineering of microorganisms for amino acid production
journal, October 2008

Dynamic modeling of the central carbon metabolism ofEscherichia coli
journal, May 2002

Hybrid dynamic modeling of Escherichia coli central metabolic network combining Michaelis–Menten and approximate kinetic equations
journal, May 2010

Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli
journal, May 2005

Expanding the chemical palate of cells by combining systems biology and metabolic engineering
journal, July 2012

In silico aided metabolic engineering of Saccharomyces cerevisiae for improved bioethanol production
journal, November 2005

OptStrain: A computational framework for redesign of microbial production systems
journal, November 2004

Enhancing sesquiterpene production in Saccharomyces cerevisiae through in silico driven metabolic engineering
journal, November 2009

Systems metabolic engineering of microorganisms for natural and non-natural chemicals
journal, May 2012

Modeling of uncertainties in biochemical reactions
journal, October 2010

Metabolic Engineering from a Cybernetic Perspective. 1. Theoretical Preliminaries
journal, June 1999

k-Cone Analysis: Determining All Candidate Values for Kinetic Parameters on a Network Scale
journal, March 2005

Integrating metabolic, transcriptional regulatory and signal transduction models in Escherichia coli
journal, July 2008

Integrated stoichiometric, thermodynamic and kinetic modelling of steady state metabolism
journal, June 2010

An integrated computational environment for elementary modes analysis of biochemical networks
journal, January 2012

Application of dynamic flux balance analysis to an industrial Escherichia coli fermentation
journal, March 2010

Effect of lpdA gene knockout on the metabolism in Escherichia coli based on enzyme activities, intracellular metabolite concentrations and metabolic flux analysis by 13C-labeling experiments
journal, March 2006

Structural kinetic modeling of metabolic networks
journal, July 2006

Genome-scale dynamic modeling of the competition between Rhodoferax and Geobacter in anoxic subsurface environments
journal, July 2010

Full-scale model of glycolysis in Saccharomyces cerevisiae
journal, December 2001

Genome-scale metabolic network modeling results in minimal interventions that cooperatively force carbon flux towards malonyl-CoA
journal, September 2011

Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids
journal, March 2007

Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data
journal, December 2010

Analysis of optimality in natural and perturbed metabolic networks
journal, November 2002

Ensemble Modeling for Aromatic Production in Escherichia coli
journal, September 2009

A genome‐scale metabolic reconstruction for Escherichia coli K‐12 MG1655 that accounts for 1260 ORFs and thermodynamic information
journal, January 2007

Predicting metabolic engineering knockout strategies for chemical production: accounting for competing pathways
journal, December 2009

Tolerance and Specificity of Recombinant 6-Methylsalicylic Acid Synthase
journal, April 1999

Genome-scale models of bacterial metabolism: reconstruction and applications
journal, January 2009

Dynamic Analysis of Integrated Signaling, Metabolic, and Regulatory Networks
journal, May 2008

Metabolic Engineering from a Cybernetic Perspective: Aspartate Family of Amino Acids
journal, January 1999

Deoxygenation of Polyhydroxybenzenes: An Alternative Strategy for the Benzene-Free Synthesis of Aromatic Chemicals
journal, May 2002

Constraints-based genome-scale metabolic simulation for systems metabolic engineering
journal, November 2009

Genome-scale metabolic modeling of a clostridial co-culture for consolidated bioprocessing
journal, July 2010

Metabolic engineering of lactic acid bacteria, the combined approach: kinetic modelling, metabolic control and experimental analysis The GenBank accession number for the sequence reported in this paper is AY046926.
journal, April 2002