Advances in metabolic pathway and strain engineering paving the way for sustainable production of chemical building blocks.

Bio-based production of chemical building blocks from renewable resources is an attractive alternative to petroleum-based platform chemicals. Metabolic pathway and strain engineering is the key element in constructing robust microbial chemical factories within the constraints of cost effective production. Here we discuss how the development of computational algorithms, novel modules and methods, omics-based techniques combined with modeling refinement are enabling reduction in development time and thus advance the field of industrial biotechnology. We further discuss how recent technological developments contribute to the development of novel cell factories for the production of the building block chemicals: adipic acid, succinic acid and 3-hydroxypropionic acid.

[1]  Jens Nielsen,et al.  Diversion of Flux toward Sesquiterpene Production in Saccharomyces cerevisiae by Fusion of Host and Heterologous Enzymes , 2010, Applied and Environmental Microbiology.

[2]  Vinod Kumar,et al.  Production of 3‐hydroxypropionic acid from glycerol by recombinant Klebsiella pneumoniae ΔdhaTΔyqhD which can produce vitamin B12 naturally , 2013, Biotechnology and bioengineering.

[3]  Sang Yup Lee,et al.  In Silico Identification of Gene Amplification Targets for Improvement of Lycopene Production , 2010, Applied and Environmental Microbiology.

[4]  J. Keasling,et al.  Engineering microbial biofuel tolerance and export using efflux pumps , 2011, Molecular systems biology.

[5]  W. Burgstaller,et al.  Succinate synthesis and excretion by Penicillium simplicissimum under aerobic and anaerobic conditions. , 2002, FEMS microbiology letters.

[6]  J. Keasling,et al.  Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids , 2012, Nature Biotechnology.

[7]  Chelladurai Rathnasingh,et al.  Development and evaluation of efficient recombinant Escherichia coli strains for the production of 3‐hydroxypropionic acid from glycerol , 2009, Biotechnology and bioengineering.

[8]  Alexander Vainstein,et al.  Harnessing yeast subcellular compartments for the production of plant terpenoids. , 2011, Metabolic engineering.

[9]  Pao-Yang Chen,et al.  Evolution, genomic analysis, and reconstruction of isobutanol tolerance in Escherichia coli , 2010, Molecular systems biology.

[10]  G. Stephanopoulos,et al.  Tuning genetic control through promoter engineering. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Kristala L J Prather,et al.  Microbial chemical factories: recent advances in pathway engineering for synthesis of value added chemicals. , 2011, Current opinion in structural biology.

[12]  Michael J. Buck,et al.  The Stress Response Factors Yap6, Cin5, Phd1, and Skn7 Direct Targeting of the Conserved Co-Repressor Tup1-Ssn6 in S. cerevisiae , 2011, PloS one.

[13]  Masayuki Inui,et al.  An efficient succinic acid production process in a metabolically engineered Corynebacterium glutamicum strain , 2008, Applied Microbiology and Biotechnology.

[14]  Ryan T Gill,et al.  Rapid profiling of a microbial genome using mixtures of barcoded oligonucleotides , 2010, Nature Biotechnology.

[15]  Chunhui Li,et al.  Exploring the diversity of complex metabolic networks , 2005, Bioinform..

[16]  Christina D Smolke,et al.  A synthetic library of RNA control modules for predictable tuning of gene expression in yeast , 2011, Molecular systems biology.

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

[18]  Kechun Zhang,et al.  Expanding metabolism for total biosynthesis of the nonnatural amino acid L-homoalanine , 2010, Proceedings of the National Academy of Sciences.

[19]  D. Weuster‐Botz,et al.  Metabolic engineering of Saccharomyces cerevisiae for the biotechnological production of succinic acid. , 2010, Metabolic engineering.

[20]  Farren J. Isaacs,et al.  Programming cells by multiplex genome engineering and accelerated evolution , 2009, Nature.

[21]  Jens Nielsen,et al.  Unravelling evolutionary strategies of yeast for improving galactose utilization through integrated systems level analysis , 2011, Proceedings of the National Academy of Sciences.

[22]  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.

[23]  B. Shanks,et al.  Platform biochemicals for a biorenewable chemical industry. , 2008, The Plant journal : for cell and molecular biology.

[24]  Jens Nielsen,et al.  Enhancing the copy number of episomal plasmids in Saccharomyces cerevisiae for improved protein production. , 2012, FEMS yeast research.

[25]  Gregory Stephanopoulos,et al.  Xylose isomerase overexpression along with engineering of the pentose phosphate pathway and evolutionary engineering enable rapid xylose utilization and ethanol production by Saccharomyces cerevisiae. , 2012, Metabolic engineering.

[26]  M. Xian,et al.  Biosynthetic pathways for 3-hydroxypropionic acid production , 2009, Applied Microbiology and Biotechnology.

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

[28]  V. Hatzimanikatis,et al.  Discovery and analysis of novel metabolic pathways for the biosynthesis of industrial chemicals: 3‐hydroxypropanoate , 2010, Biotechnology and bioengineering.

[29]  Michael Bott,et al.  Toward Homosuccinate Fermentation: Metabolic Engineering of Corynebacterium glutamicum for Anaerobic Production of Succinate from Glucose and Formate , 2012, Applied and Environmental Microbiology.

[30]  K. Shimizu,et al.  Simultaneous production of 3-hydroxypropionic acid and 1,3-propanediol from glycerol by a recombinant strain of Klebsiella pneumoniae. , 2012, Bioresource technology.

[31]  Keith E. J. Tyo,et al.  Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli , 2010, Science.

[32]  Alfonso Jaramillo,et al.  DESHARKY: automatic design of metabolic pathways for optimal cell growth , 2008, Bioinform..

[33]  V. Siewers,et al.  A systems-level approach for metabolic engineering of yeast cell factories. , 2012, FEMS yeast research.

[34]  Philippe Soucaille,et al.  A new process for the continuous production of succinic acid from glucose at high yield, titer, and productivity , 2008, Biotechnology and bioengineering.

[35]  Thomas Jeffries,et al.  Shuffling of Promoters for Multiple Genes To Optimize Xylose Fermentation in an Engineered Saccharomyces cerevisiae Strain , 2007, Applied and Environmental Microbiology.

[36]  K. Patil,et al.  Enhancing sesquiterpene production in Saccharomyces cerevisiae through in silico driven metabolic engineering. , 2009, Metabolic engineering.

[37]  S. Tringe,et al.  Metagenomic Discovery of Biomass-Degrading Genes and Genomes from Cow Rumen , 2011, Science.

[38]  B. Palsson,et al.  Constraining the metabolic genotype–phenotype relationship using a phylogeny of in silico methods , 2012, Nature Reviews Microbiology.

[39]  J. Keasling,et al.  Targeted proteomics for metabolic pathway optimization: application to terpene production. , 2011, Metabolic engineering.

[40]  Jay D Keasling,et al.  BglBricks: A flexible standard for biological part assembly , 2010, Journal of biological engineering.

[41]  M. Bott,et al.  Toward biotechnological production of adipic acid and precursors from biorenewables. , 2013, Journal of biotechnology.

[42]  Brian F. Pfleger,et al.  Application of Functional Genomics to Pathway Optimization for Increased Isoprenoid Production , 2008, Applied and Environmental Microbiology.

[43]  S. M. Raj,et al.  Production of 3-hydroxypropionic acid via malonyl-CoA pathway using recombinant Escherichia coli strains. , 2012, Journal of biotechnology.

[44]  Pablo Carbonell,et al.  A retrosynthetic biology approach to metabolic pathway design for therapeutic production , 2011, BMC Systems Biology.

[45]  Z. P. Çakar,et al.  Evolutionary engineering of Saccharomyces cerevisiae for improved industrially important properties. , 2012, FEMS yeast research.

[46]  C. Wittmann,et al.  From zero to hero--design-based systems metabolic engineering of Corynebacterium glutamicum for L-lysine production. , 2011, Metabolic engineering.

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

[48]  David Baker,et al.  De Novo Enzyme Design Using Rosetta3 , 2011, PloS one.

[49]  G. Stephanopoulos,et al.  Engineering Yeast Transcription Machinery for Improved Ethanol Tolerance and Production , 2006, Science.

[50]  A. Schirmer,et al.  Microbial Biosynthesis of Alkanes , 2010, Science.

[51]  Vinod Kumar,et al.  Effect of puuC overexpression and nitrate addition on glycerol metabolism and anaerobic 3-hydroxypropionic acid production in recombinant Klebsiella pneumoniae ΔglpKΔdhaT. , 2013, Metabolic engineering.

[52]  S. P. Sineoky,et al.  Production of succinic acid at low pH by a recombinant strain of the aerobic yeast Yarrowia lipolytica , 2010, Biotechnology and bioengineering.

[53]  Xuebing Zhao,et al.  Biotechnological production of succinic acid: current state and perspectives , 2012 .

[54]  Faisal A. Aldaye,et al.  Identity : Key to Children ’ s Understanding of Belief , 2013 .

[55]  Ryan T Gill,et al.  SCALEs: multiscale analysis of library enrichment , 2007, Nature Methods.

[56]  Huimin Zhao,et al.  Rapid characterization and engineering of natural product biosynthetic pathways via DNA assembler. , 2011, Molecular bioSystems.

[57]  Christopher A. Voigt,et al.  Automated Design of Synthetic Ribosome Binding Sites to Precisely Control Protein Expression , 2009, Nature Biotechnology.

[58]  Intawat Nookaew,et al.  BioMet Toolbox: genome-wide analysis of metabolism , 2010, Nucleic Acids Res..

[59]  Thomas H Segall-Shapiro,et al.  Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome , 2010, Science.

[60]  Sunwon Park,et al.  Prediction of novel synthetic pathways for the production of desired chemicals , 2010, BMC Systems Biology.

[61]  Chelladurai Rathnasingh,et al.  Development of recombinant Klebsiella pneumoniae ∆dhaT strain for the co-production of 3-hydroxypropionic acid and 1,3-propanediol from glycerol , 2011, Applied Microbiology and Biotechnology.

[62]  S. Elledge,et al.  Harnessing homologous recombination in vitro to generate recombinant DNA via SLIC , 2007, Nature Methods.

[63]  Gabriel C. Wu,et al.  Synthetic protein scaffolds provide modular control over metabolic flux , 2009, Nature Biotechnology.

[64]  Kelly M. Thayer,et al.  Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control , 2010, Proceedings of the National Academy of Sciences.

[65]  Costas D Maranas,et al.  OptStrain: a computational framework for redesign of microbial production systems. , 2004, Genome research.