In Silico Design Strategies for the Production of Target Chemical Compounds Using Iterative Single-Level Linear Programming Problems

The optimization of metabolic reaction modifications for the production of target compounds is a complex computational problem whose execution time increases exponentially with the number of metabolic reactions. Therefore, practical technologies are needed to identify reaction deletion combinations to minimize computing times and promote the production of target compounds by modifying intracellular metabolism. In this paper, a practical metabolic design technology named AERITH is proposed for high-throughput target compound production. This method can optimize the production of compounds of interest while maximizing cell growth. With this approach, an appropriate combination of metabolic reaction deletions can be identified by solving a simple linear programming problem. Using a standard CPU, the computation time could be as low as 1 min per compound, and the system can even handle large metabolic models. AERITH was implemented in MATLAB and is freely available for non-profit use.

[1]  A. Kondo,et al.  Direct 1,3-butadiene biosynthesis in Escherichia coli via a tailored ferulic acid decarboxylase mutant , 2020, Nature Communications.

[2]  Christopher P. Long,et al.  High-resolution 13C metabolic flux analysis , 2019, Nature Protocols.

[3]  C. Delpino,et al.  In silico strategies to couple production of bioethanol with growth in cyanobacteria , 2019, Biotechnology and bioengineering.

[4]  Gi Bae Kim,et al.  Current status and applications of genome-scale metabolic models , 2019, Genome Biology.

[5]  Douglas C. Friedman,et al.  Building a global alliance of biofoundries , 2019, Nature Communications.

[6]  E. P. Hudson,et al.  Computational metabolic engineering strategies for growth-coupled biofuel production by Synechocystis , 2016, Metabolic engineering communications.

[7]  Yanhe Ma,et al.  Fermentative production of enantiomerically pure S-1,2-propanediol from glucose by engineered E. coli strain , 2016, Applied Microbiology and Biotechnology.

[8]  Jens Nielsen,et al.  Production of natural products through metabolic engineering of Saccharomyces cerevisiae. , 2015, Current opinion in biotechnology.

[9]  J. Sanders,et al.  Metabolic engineering of the mixed-acid fermentation pathway of Escherichia coli for anaerobic production of glutamate and itaconate , 2015, AMB Express.

[10]  Desmond S Lun,et al.  Constraint‐based modeling of heterologous pathways: Application and experimental demonstration for overproduction of fatty acids in Escherichia coli , 2014, Biotechnology and bioengineering.

[11]  Hiroshi Shimizu,et al.  FastPros: screening of reaction knockout strategies for metabolic engineering , 2013, Bioinform..

[12]  R. K. De,et al.  Comparing methods for metabolic network analysis and an application to metabolic engineering. , 2013, Gene.

[13]  Ali R. Zomorrodi,et al.  Mathematical optimization applications in metabolic networks. , 2012, Metabolic engineering.

[14]  Desmond S. Lun,et al.  Truncated branch and bound achieves efficient constraint-based genetic design , 2012, Bioinform..

[15]  G. Bennett,et al.  Succinate production in Escherichia coli , 2012, Biotechnology journal.

[16]  M. Oh,et al.  Production of 2,3-butanediol in Saccharomyces cerevisiae by in silico aided metabolic engineering , 2011, Microbial Cell Factories.

[17]  A. Burgard,et al.  Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol. , 2011, Nature chemical biology.

[18]  J. Keasling.  Manufacturing Molecules Through Metabolic Engineering , 2010, Science.

[19]  L. Reitzer,et al.  Genetics and Regulation of the Major Enzymes of Alanine Synthesis in Escherichia coli , 2010, Journal of bacteriology.

[20]  Miguel Rocha,et al.  OptFlux: an open-source software platform for in silico metabolic engineering , 2010, BMC Systems Biology.

[21]  Costas D. Maranas,et al.  OptForce: An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions , 2010, PLoS Comput. Biol..

[22]  Tomer Shlomi,et al.  Predicting metabolic engineering knockout strategies for chemical production: accounting for competing pathways , 2010, Bioinform..

[23]  U. Sauer,et al.  13C-based metabolic flux analysis , 2009, Nature Protocols.

[24]  B. Williams,et al.  Mapping and quantifying mammalian transcriptomes by RNA-Seq , 2008, Nature Methods.

[25]  Xueli Zhang,et al.  Combining metabolic engineering and metabolic evolution to develop nonrecombinant strains of Escherichia coli C that produce succinate and malate , 2008, Biotechnology and bioengineering.

[26]  Xueli Zhang,et al.  Production of l-alanine by metabolically engineered Escherichia coli , 2007, Applied Microbiology and Biotechnology.

[27]  Adam M. Feist,et al.  A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information , 2007, Molecular systems biology.

[28]  B. Palsson,et al.  Metabolic analysis of adaptive evolution for in silico‐designed lactate‐producing strains , 2006, Biotechnology and bioengineering.

[29]  Jens Nielsen,et al.  Evolutionary programming as a platform for in silico metabolic engineering , 2005, BMC Bioinformatics.

[30]  A. Burgard,et al.  Optknock: A bilevel programming framework for identifying gene knockout strategies for microbial strain optimization , 2003, Biotechnology and bioengineering.

[31]  Mee-Jung Han,et al.  Proteome Analysis of Metabolically EngineeredEscherichia coli Producing Poly(3-Hydroxybutyrate) , 2000, Journal of bacteriology.

[32]  Douglas C. Cameron,et al.  Metabolic Engineering of a 1,2-Propanediol Pathway in Escherichia coli , 1999, Applied and Environmental Microbiology.

[33]  B. Palsson,et al.  Metabolic Flux Balancing: Basic Concepts, Scientific and Practical Use , 1994, Bio/Technology.

[34]  H C Lim,et al.  Acetic acid formation in escherichia coli fermentation , 1992, Biotechnology and bioengineering.

[35]  Myron D. Maker,et al.  Hydrogen Sulfide-Producing Variants of Escherichia coli , 1974 .

[36]  D. Morris,et al.  Urea Production and Putrescine Biosynthesis by Escherichia coli , 1967, Journal of bacteriology.

[37]  K. Kim,et al.  Optimization of hexanoic acid production in recombinant Escherichia coli by precise flux rebalancing. , 2018, Bioresource technology.

[38]  Shivakumar Keerthikumar,et al.  An Introduction to Proteome Bioinformatics. , 2017, Methods in molecular biology.

[39]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[40]  Ronan M. T. Fleming,et al.  Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0 , 2007, Nature Protocols.

[41]  Adam M. Feist,et al.  A comprehensive genome-scale reconstruction of Escherichia coli metabolism—2011 , 2011, Molecular systems biology.