Skip to main content
SpringerLink
Log in

Pathway Design, Engineering, and Optimization

  • Chapter
  • First Online:
Synthetic Biology – Metabolic Engineering

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 162))

Abstract

The microbial metabolic versatility found in nature has inspired scientists to create microorganisms capable of producing value-added compounds. Many endeavors have been made to transfer and/or combine pathways, existing or even engineered enzymes with new function to tractable microorganisms to generate new metabolic routes for drug, biofuel, and specialty chemical production. However, the success of these pathways can be impeded by different complications from an inherent failure of the pathway to cell perturbations. Pursuing ways to overcome these shortcomings, a wide variety of strategies have been developed. This chapter will review the computational algorithms and experimental tools used to design efficient metabolic routes, and construct and optimize biochemical pathways to produce chemicals of high interest.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lee JW, Na D, Park JM, Lee J, Choi S, Lee SY (2012) Systems metabolic engineering of microorganisms for natural and non-natural chemicals. Nat Chem Biol 8(6):536–546

    Article  CAS  Google Scholar 

  2. Dai Z, Nielsen J (2015) Advancing metabolic engineering through systems biology of industrial microorganisms. Curr Opin Biotechnol 36:8–15

    Article  CAS  Google Scholar 

  3. Chen Y, Nielsen J (2013) Advances in metabolic pathway and strain engineering paving the way for sustainable production of chemical building blocks. Curr Opin Biotechnol 24(6):965–972

    Article  CAS  Google Scholar 

  4. Liu Y, Shin H-d, Li J, Liu L (2015) Toward metabolic engineering in the context of system biology and synthetic biology: advances and prospects. Appl Microbiol Biotechnol 99(3):1109–1118

    Article  CAS  Google Scholar 

  5. Du J, Shao Z, Zhao H (2011) Engineering microbial factories for synthesis of value-added products. J Ind Microbiol Biotechnol 38(8):873–890

    Article  CAS  Google Scholar 

  6. Eriksen DT, Li S, Zhao H (2013) Chapter 3 - Pathway engineering as an enabling synthetic biology tool. In: Zhao H (ed) Synthetic biology. Academic, Boston, pp 43–61

    Chapter  Google Scholar 

  7. Jones JA, Toparlak ÖD, Koffas MAG (2015) Metabolic pathway balancing and its role in the production of biofuels and chemicals. Curr Opin Biotechnol 33:52–59

    Article  CAS  Google Scholar 

  8. Soma Y, Tsuruno K, Wada M, Yokota A, Hanai T (2014) Metabolic flux redirection from a central metabolic pathway toward a synthetic pathway using a metabolic toggle switch. Metab Eng 23:175–184

    Article  CAS  Google Scholar 

  9. Lee SY, Kim HU (2015) Systems strategies for developing industrial microbial strains. Nat Biotechnol 33(10):1061–1072

    Article  CAS  Google Scholar 

  10. Si T, HamediRad M, Zhao H (2015) Regulatory RNA-assisted genome engineering in microorganisms. Curr Opin Biotechnol 36:85–90

    Article  CAS  Google Scholar 

  11. Fernández-Castané A, Fehér T, Carbonell P, Pauthenier C, Faulon J-L (2014) Computer-aided design for metabolic engineering. J Biotechnol 192 Part B:302–313

    Google Scholar 

  12. Tai M, Stephanopoulos G (2013) Engineering the push and pull of lipid biosynthesis in oleaginous yeast Yarrowia lipolytica for biofuel production. Metab Eng 15:1–9

    Article  CAS  Google Scholar 

  13. Lian J, Li Y, HamediRad M, Zhao H (2014) Directed evolution of a cellodextrin transporter for improved biofuel production under anaerobic conditions in Saccharomyces cerevisiae. Biotechnol Bioeng 111(8):1521–1531

    Article  CAS  Google Scholar 

  14. Sun J, Wen F, Si T, Xu J-H, Zhao H (2012) Direct conversion of xylan to ethanol by recombinant Saccharomyces cerevisiae strains displaying an engineered minihemicellulosome. Appl Environ Microbiol 78(11):3837–3845

    Article  CAS  Google Scholar 

  15. Kim SR, Skerker JM, Kang W, Lesmana A, Wei N, Arkin AP, Jin Y-S (2013) Rational and evolutionary engineering approaches uncover a small set of genetic changes efficient for rapid xylose fermentation in Saccharomyces cerevisiae. PLoS One 8(2), e57048

    Article  CAS  Google Scholar 

  16. Rutter C, Zhang S, Rao C (2015) Engineering Yarrowia lipolytica for production of medium-chain fatty acids. Appl Microbiol Biotechnol 99(17):7359–7368

    Article  CAS  Google Scholar 

  17. Eriksen DT, HamediRad M, Yuan Y, Zhao H (2015) Orthogonal fatty acid biosynthetic pathway improves fatty acid ethyl ester production in Saccharomyces cerevisiae. ACS Synth Biol 4(7):808–814

    Article  CAS  Google Scholar 

  18. Feng X, Lian J, Zhao H (2015) Metabolic engineering of Saccharomyces cerevisiae to improve 1-hexadecanol production. Metab Eng 27:10–19

    Article  CAS  Google Scholar 

  19. Freestone TS, Zhao H (2016) Combinatorial pathway engineering for optimized production of the anti-malarial FR900098. Biotechnol Bioeng 113(2):384–392

    Article  CAS  Google Scholar 

  20. Lian J, Si T, Nair NU, Zhao H (2014) Design and construction of acetyl-CoA overproducing Saccharomyces cerevisiae strains. Metab Eng 24:139–149

    Google Scholar 

  21. Fisher AK, Freedman BG, Bevan DR, Senger RS (2014) A review of metabolic and enzymatic engineering strategies for designing and optimizing performance of microbial cell factories. Comput Struct Biotechnol J 11(18):91–99

    Article  Google Scholar 

  22. Jardine O, Gough J, Chothia C, Teichmann SA (2002) Comparison of the small molecule metabolic enzymes of Escherichia coli and Saccharomyces cerevisiae. Genome Res 12(6):916–929

    Article  CAS  Google Scholar 

  23. Feng X, Zhao H (2013) Investigating host dependence of xylose utilization in recombinant Saccharomyces cerevisiae strains using RNA-seq analysis. Biotechnol Biofuels 6(1):1–17

    Article  CAS  Google Scholar 

  24. Schomburg I, Chang A, Placzek S, Söhngen C, Rother M, Lang M, Munaretto C, Ulas S, Stelzer M, Grote A, Scheer M, Schomburg D (2013) BRENDA in 2013: integrated reactions, kinetic data, enzyme function data, improved disease classification: new options and contents in BRENDA. Nucleic Acids Res 41(D1):D764–D772

    Article  CAS  Google Scholar 

  25. Henry CS, Broadbelt LJ, Hatzimanikatis V (2010) Discovery and analysis of novel metabolic pathways for the biosynthesis of industrial chemicals: 3-hydroxypropanoate. Biotechnol Bioeng 106(3):462–473

    CAS  Google Scholar 

  26. Fehér T, Planson A-G, Carbonell P, Fernández-Castané A, Grigoras I, Dariy E, Perret A, Faulon J-L (2014) Validation of RetroPath, a computer-aided design tool for metabolic pathway engineering. Biotechnol J 9(11):1446–1457

    Article  CAS  Google Scholar 

  27. Salis HM, Mirsky EA, Voigt CA (2009) Automated design of synthetic ribosome binding sites to control protein expression. Nat Biotechnol 27(10):946–950

    Article  CAS  Google Scholar 

  28. Farasat I, Kushwaha M, Collens J, Easterbrook M, Guido M, Salis HM (2014) Efficient search, mapping, and optimization of multi-protein genetic systems in diverse bacteria. Mol Syst Biol 10(6):731

    Article  CAS  Google Scholar 

  29. Chao R, Yuan Y, Zhao H (2015) Recent advances in DNA assembly technologies. FEMS Yeast Res 15(1):1–9

    Article  Google Scholar 

  30. Gibson DG, Young L, Chuang R-Y, Venter JC, Hutchison CA, Smith HO (2009) Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods 6(5):343–345

    Article  CAS  Google Scholar 

  31. Cobb R, Ning J, Zhao H (2014) DNA assembly techniques for next-generation combinatorial biosynthesis of natural products. J Ind Microbiol Biotechnol 41(2):469–477

    Article  CAS  Google Scholar 

  32. Rebatchouk D, Daraselia N, Narita JO (1996) NOMAD: a versatile strategy for in vitro DNA manipulation applied to promoter analysis and vector design. Proc Natl Acad Sci U S A 93(20):10891–10896

    Article  CAS  Google Scholar 

  33. Shetty RP, Endy D, Knight TF (2008) Engineering BioBrick vectors from BioBrick parts. J Biol Eng 2(1):1–12

    Article  CAS  Google Scholar 

  34. Xu P, Vansiri A, Bhan N, Koffas MAG (2012) ePathBrick: a synthetic biology platform for engineering metabolic pathways in E. coli. ACS Synth Biol 1(7):256–266

    Article  CAS  Google Scholar 

  35. Zhao S, Jones JA, Lachance DM, Bhan N, Khalidi O, Venkataraman S, Wang Z, Koffas MAG (2015) Improvement of catechin production in Escherichia coli through combinatorial metabolic engineering. Metab Eng 28:43–53

    Article  CAS  Google Scholar 

  36. Xu P, Gu Q, Wang W, Wong L, Bower AGW, Collins CH, Koffas MAG (2013) Modular optimization of multi-gene pathways for fatty acids production in E. coli. Nat Commun 4:1409

    Google Scholar 

  37. Liu J-K, Chen W-H, Ren S-X, Zhao G-P, Wang J (2014) iBrick: a new standard for iterative assembly of biological parts with homing endonucleases. PLoS One 9(10), e110852

    Article  CAS  Google Scholar 

  38. Gibson DG, Smith HO (2010) Method for in vitro recombination. US 7,776,532 B2

    Google Scholar 

  39. Gibson DG, Smith HO, Hutchison CA, Young L, Venter JC (2015) Methods for in vitro joining and combinatorial assembly of nucleic acid molecules. US 8,968,999 B2

    Google Scholar 

  40. Gibson DG, Benders GA, Andrews-Pfannkoch C, Denisova EA, Baden-Tillson H, Zaveri J, Stockwell TB, Brownley A, Thomas DW, Algire MA, Merryman C, Young L, Noskov VN, Glass JI, Venter JC, Hutchison CA, Smith HO (2008) Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome. Science 319(5867):1215–1220

    Article  CAS  Google Scholar 

  41. Sleight SC, Sauro HM (2013) Randomized BioBrick assembly: a novel DNA assembly method for randomizing and optimizing genetic circuits and metabolic pathways. ACS Synth Biol 2(9):506–518

    Article  CAS  Google Scholar 

  42. Sd K, Stanton LH, Slaby T, Durot M, Holmes VF, Patel KG, Platt D, Shapland EB, Serber Z, Dean J, Newman JD, Chandran SS (2014) Rapid and reliable DNA assembly via ligase cycling reaction. ACS Synth Biol 3(2):97–106

    Article  CAS  Google Scholar 

  43. Engler C, Kandzia R, Marillonnet S (2008) A one pot, one step, precision cloning method with high throughput capability. PLoS One 3(11), e3647

    Article  CAS  Google Scholar 

  44. Liang J, Chao R, Abil Z, Bao Z, Zhao H (2014) FairyTALE: a high-throughput TAL effector synthesis platform. ACS Synth Biol 3(2):67–73

    Article  CAS  Google Scholar 

  45. Weber E, Engler C, Gruetzner R, Werner S, Marillonnet S (2011) A modular cloning system for standardized assembly of multigene constructs. PLoS One 6(2), e16765

    Article  CAS  Google Scholar 

  46. Weber E, Werner S, Engler C, Gruetzner R, Marillonnet S (2011) System and method of modular cloning. EP 2,395,087 A1

    Google Scholar 

  47. Lee ME, DeLoache WC, Cervantes B, Dueber JE (2015) A highly characterized yeast toolkit for modular, multipart assembly. ACS Synth Biol 4(9):975–986

    Article  CAS  Google Scholar 

  48. Iverson SV, Haddock TL, Beal J, Densmore DM (2016) CIDAR MoClo: improved MoClo assembly standard and new E. coli part library enable rapid combinatorial design for synthetic and traditional biology. ACS Synth Biol 5(1):99–103

    Article  CAS  Google Scholar 

  49. Shao Z, Zhao H, Zhao H (2009) DNA assembler, an in vivo genetic method for rapid construction of biochemical pathways. Nucleic Acids Res 37(2):e16

    Article  CAS  Google Scholar 

  50. Kuijpers NGA, Solis-Escalante D, Bosman L, van den Broek M, Pronk JT, Daran J-M, Daran-Lapujade P (2013) A versatile, efficient strategy for assembly of multi-fragment expression vectors in Saccharomyces cerevisiae using 60 bp synthetic recombination sequences. Microb Cell Fact 12:47

    Article  CAS  Google Scholar 

  51. Shao Z, Zhao H (2014) Manipulating natural product biosynthetic pathways via DNA assembler. Curr Protoc Chem Biol 6(2):65–100

    Article  Google Scholar 

  52. Shao Z, Zhao H (2013) Construction and engineering of large biochemical pathways via DNA assembler. In: Polizzi KM, Kontoravdi C (eds) Synthetic biology. Methods in molecular biology, vol 1073. Humana Press, New York, pp 85–106

    Chapter  Google Scholar 

  53. Shao Z, Zhao H (2012) Chapter Ten – DNA assembler: a synthetic biology tool for characterizing and engineering natural product gene clusters. In: David AH (ed) Methods in enzymology, vol 517. Academic Press, San Diego, pp 203–224

    Google Scholar 

  54. Shao Z, Luo Y, Zhao H (2012) DNA assembler method for construction of zeaxanthin-producing strains of Saccharomyces cerevisiae. In: Barredo J-L (ed) Microbial carotenoids from fungi. Methods in molecular biology, vol 898. Humana Press, New York, pp 251–262

    Chapter  Google Scholar 

  55. Mitchell LA, Chuang J, Agmon N, Khunsriraksakul C, Phillips NA, Cai Y, Truong DM, Veerakumar A, Wang Y, Mayorga M, Blomquist P, Sadda P, Trueheart J, Boeke JD (2015) Versatile genetic assembly system (VEGAS) to assemble pathways for expression in S. cerevisiae. Nucleic Acids Res 43(13):6620–6630

    Article  CAS  Google Scholar 

  56. Yuan Y, Andersen E, Zhao H (2016) Flexible and versatile strategy for the construction of large biochemical pathways. ACS Synth Biol 5(1):46–52

    Article  CAS  Google Scholar 

  57. Hillson NJ, Rosengarten RD, Keasling JD (2012) j5 DNA assembly design automation software. ACS Synth Biol 1(1):14–21

    Article  CAS  Google Scholar 

  58. Hillson N (2014) j5 DNA assembly design automation. In: Valla S, Lale R (eds) DNA cloning and assembly methods. Methods in molecular biology, vol 1116. Humana Press, New York, pp 245–269

    Chapter  Google Scholar 

  59. Appleton E, Tao J, Haddock T, Densmore D (2014) Interactive assembly algorithms for molecular cloning. Nat Methods 11(6):657–662

    Article  CAS  Google Scholar 

  60. Lin Y, Sun X, Yuan Q, Yan Y (2014) Extending shikimate pathway for the production of muconic acid and its precursor salicylic acid in Escherichia coli. Metab Eng 23:62–69

    Article  CAS  Google Scholar 

  61. Jones KL, Kim S-W, Keasling JD (2000) Low-copy plasmids can perform as well as or better than high-copy plasmids for metabolic engineering of bacteria. Metab Eng 2(4):328–338

    Article  CAS  Google Scholar 

  62. Lee TH, Maheshri N (2012) A regulatory role for repeated decoy transcription factor binding sites in target gene expression. Mol Syst Biol 8(1)

    Google Scholar 

  63. Wu J, Liu P, Fan Y, Bao H, Du G, Zhou J, Chen J (2013) Multivariate modular metabolic engineering of Escherichia coli to produce resveratrol from L-tyrosine. J Biotechnol 167(4):404–411

    Article  CAS  Google Scholar 

  64. Yin J, Wang H, Fu X-Z, Gao X, Wu Q, Chen G-Q (2015) Effects of chromosomal gene copy number and locations on polyhydroxyalkanoate synthesis by Escherichia coli and Halomonas sp. Appl Microbiol Biotechnol 99(13):5523–5534

    Article  CAS  Google Scholar 

  65. Da Silva NA, Srikrishnan S (2012) Introduction and expression of genes for metabolic engineering applications in Saccharomyces cerevisiae. FEMS Yeast Res 12(2):197–214

    Article  CAS  Google Scholar 

  66. Karim AS, Curran KA, Alper HS (2013) Characterization of plasmid burden and copy number in Saccharomyces cerevisiae for optimization of metabolic engineering applications. FEMS Yeast Res 13(1):107–116

    Article  CAS  Google Scholar 

  67. Gu P, Yang F, Su T, Wang Q, Liang Q, Qi Q (2015) A rapid and reliable strategy for chromosomal integration of gene(s) with multiple copies. Sci Rep 5:9684

    Article  CAS  Google Scholar 

  68. Lee TJ, Parikh RY, Weitz JS, Kim HD (2014) Suppression of expression between adjacent genes within heterologous modules in yeast. G3 (Bethesda) 4(1):109–116

    Article  CAS  Google Scholar 

  69. Santos CNS, Regitsky DD, Yoshikuni Y (2013) Implementation of stable and complex biological systems through recombinase-assisted genome engineering. Nat Commun 4

    Google Scholar 

  70. Santos CNS, Yoshikuni Y (2014) Engineering complex biological systems in bacteria through recombinase-assisted genome engineering. Nat Protoc 9(6):1320–1336

    Article  CAS  Google Scholar 

  71. Jakočiūnas T, Rajkumar AS, Zhang J, Arsovska D, Rodriguez A, Jendresen CB, Skjødt ML, Nielsen AT, Borodina I, Jensen MK, Keasling JD (2015) CasEMBLR: Cas9-Facilitated multiloci genomic integration of in vivo assembled DNA parts in Saccharomyces cerevisiae. ACS Synth Biol 4(11):1226–1234

    Google Scholar 

  72. Ryan OW, Skerker JM, Maurer MJ, Li X, Tsai JC, Poddar S, Lee ME, DeLoache W, Dueber JE, Arkin AP, Cate JH (2014) Selection of chromosomal DNA libraries using a multiplex CRISPR system. eLife 3

    Google Scholar 

  73. Bao Z, Xiao H, Liang J, Zhang L, Xiong X, Sun N, Si T, Zhao H (2015) Homology-Integrated CRISPR–Cas (HI-CRISPR) system for one-step multigene disruption in Saccharomyces cerevisiae. ACS Synth Biol 4(5):585–594

    Article  CAS  Google Scholar 

  74. DiCarlo JE, Norville JE, Mali P, Rios X, Aach J, Church GM (2013) Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Res 41(7):4336–4343

    Article  CAS  Google Scholar 

  75. Shi S, Liang Y, Zhang MM, Ang EL, Zhao H (2016) A highly efficient single-step, markerless strategy for multi-copy chromosomal integration of large biochemical pathways in Saccharomyces cerevisiae. Metab Eng 33:19–27

    Article  CAS  Google Scholar 

  76. Curran KA, Crook NC, Karim AS, Gupta A, Wagman AM, Alper HS (2014) Design of synthetic yeast promoters via tuning of nucleosome architecture. Nat Commun 5

    Google Scholar 

  77. Mutalik VK, Guimaraes JC, Cambray G, Lam C, Christoffersen MJ, Mai Q-A, Tran AB, Paull M, Keasling JD, Arkin AP, Endy D (2013) Precise and reliable gene expression via standard transcription and translation initiation elements. Nat Methods 10(4):354–360

    Article  CAS  Google Scholar 

  78. Mutalik VK, Guimaraes JC, Cambray G, Mai Q-A, Christoffersen MJ, Martin L, Yu A, Lam C, Rodriguez C, Bennett G, Keasling JD, Endy D, Arkin AP (2013) Quantitative estimation of activity and quality for collections of functional genetic elements. Nat Methods 10(4):347–353

    Article  CAS  Google Scholar 

  79. Redden H, Alper HS (2015) The development and characterization of synthetic minimal yeast promoters. Nat Commun 6

    Google Scholar 

  80. Liang J, Ning JC, Zhao H (2013) Coordinated induction of multi-gene pathways in Saccharomyces cerevisiae. Nucleic Acids Res 41(4), e54

    Article  CAS  Google Scholar 

  81. Lee ME, Aswani A, Han AS, Tomlin CJ, Dueber JE (2013) Expression-level optimization of a multi-enzyme pathway in the absence of a high-throughput assay. Nucleic Acids Res 41(22):10668–10678

    Article  CAS  Google Scholar 

  82. Zhang C, Zou R, Chen X, Stephanopoulos G, Too H-P (2015) Experimental design-aided systematic pathway optimization of glucose uptake and deoxyxylulose phosphate pathway for improved amorphadiene production. Appl Microbiol Biotechnol 99(9):3825–3837

    Article  CAS  Google Scholar 

  83. Lim JH, Seo SW, Kim SY, Jung GY (2013) Refactoring redox cofactor regeneration for high-yield biocatalysis of glucose to butyric acid in Escherichia coli. Bioresour Technol 135:568–573

    Article  CAS  Google Scholar 

  84. Liu Y, Zhu Y, Li J, H-d S, Chen RR, Du G, Liu L, Chen J (2014) Modular pathway engineering of Bacillus subtilis for improved N-acetylglucosamine production. Metab Eng 23:42–52

    Article  CAS  Google Scholar 

  85. Leavitt JM, Alper HS (2015) Advances and current limitations in transcript-level control of gene expression. Curr Opin Biotechnol 34:98–104

    Article  CAS  Google Scholar 

  86. Curran KA, Karim AS, Gupta A, Alper HS (2013) Use of expression-enhancing terminators in Saccharomyces cerevisiae to increase mRNA half-life and improve gene expression control for metabolic engineering applications. Metab Eng 19:88–97

    Article  CAS  Google Scholar 

  87. Curran KA, Morse NJ, Markham KA, Wagman AM, Gupta A, Alper HS (2015) Short synthetic terminators for improved heterologous gene expression in yeast. ACS Synth Biol 4(7):824–832

    Article  CAS  Google Scholar 

  88. Qi Lei S, Larson Matthew H, Gilbert Luke A, Doudna Jennifer A, Weissman Jonathan S, Arkin Adam P, Lim Wendell A (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152(5):1173–1183

    Article  CAS  Google Scholar 

  89. Lv L, Ren Y-L, Chen J-C, Wu Q, Chen G-Q (2015) Application of CRISPRi for prokaryotic metabolic engineering involving multiple genes, a case study: Controllable P(3HB-co-4HB) biosynthesis. Metab Eng 29:160–168

    Article  CAS  Google Scholar 

  90. Gilbert Luke A, Larson Matthew H, Morsut L, Liu Z, Brar Gloria A, Torres Sandra E, Stern-Ginossar N, Brandman O, Whitehead Evan H, Doudna Jennifer A, Lim Wendell A, Weissman Jonathan S, Qi Lei S (2013) CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154(2):442–451

    Article  CAS  Google Scholar 

  91. Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M, Kosuri S, Yang L, Church GM (2013) CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol 31(9):833–838

    Article  CAS  Google Scholar 

  92. Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32(4):347–355

    Article  CAS  Google Scholar 

  93. Zalatan Jesse G, Lee Michael E, Almeida R, Gilbert Luke A, Whitehead Evan H, La Russa M, Tsai Jordan C, Weissman Jonathan S, Dueber John E, Qi Lei S, Lim Wendell A (2015) Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. Cell 160(1–2):339–350

    Article  CAS  Google Scholar 

  94. Alonso-Gutierrez J, Chan R, Batth TS, Adams PD, Keasling JD, Petzold CJ, Lee TS (2013) Metabolic engineering of Escherichia coli for limonene and perillyl alcohol production. Metab Eng 19:33–41

    Article  CAS  Google Scholar 

  95. Tong Y, Yang H, Xin Y, Zhang L, Wang W (2015) Novel integration strategy coupling codon and fermentation optimization for efficiently enhancing sarcosine oxidase (SOX) production in recombinant Escherichia coli. World J Microbiol Biotechnol 31(5):707–716

    Article  CAS  Google Scholar 

  96. Wei L, Liu J, Qi H, Wen J (2015) Engineering Scheffersomyces stipitis for fumaric acid production from xylose. Bioresour Technol 187:246–254

    Article  CAS  Google Scholar 

  97. Presnyak V, Alhusaini N, Chen Y-H, Martin S, Morris N, Kline N, Olson S, Weinberg D, Baker Kristian E, Graveley Brenton R, Coller J (2015) Codon optimality is a major determinant of mRNA stability. Cell 160(6):1111–1124

    Article  CAS  Google Scholar 

  98. Agashe D, Martinez-Gomez NC, Drummond DA, Marx CJ (2013) Good codons, bad transcript: large reductions in gene expression and fitness arising from synonymous mutations in a key enzyme. Mol Biol Evol 30(3):549–560

    Article  CAS  Google Scholar 

  99. Lanza AM, Curran KA, Rey LG, Alper HS (2014) A condition-specific codon optimization approach for improved heterologous gene expression in Saccharomyces cerevisiae. BMC Syst Biol 8:33

    Article  CAS  Google Scholar 

  100. Allert M, Cox JC, Hellinga HW (2010) Multifactorial determinants of protein expression in prokaryotic open reading frames. J Mol Biol 402(5):905–918

    Article  CAS  Google Scholar 

  101. Pop C, Rouskin S, Ingolia NT, Han L, Phizicky EM, Weissman JS, Koller D (2014) Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation. Mol Syst Biol 10(12)

    Google Scholar 

  102. Welch M, Villalobos A, Gustafsson C, Minshull J (2011) Chapter three – designing genes for successful protein expression. In: Christopher V (ed) Methods in enzymology, vol 498. Academic Press, San Diego, pp 43–66

    Google Scholar 

  103. Villalobos A, Ness J, Gustafsson C, Minshull J, Govindarajan S (2006) Gene designer: a synthetic biology tool for constructing artificial DNA segments. BMC Bioinf 7(1):285

    Article  CAS  Google Scholar 

  104. Coussement P, Maertens J, Beauprez J, Van Bellegem W, De Mey M (2014) One step DNA assembly for combinatorial metabolic engineering. Metab Eng 23:70–77

    Article  CAS  Google Scholar 

  105. Nowroozi F, Baidoo EK, Ermakov S, Redding-Johanson A, Batth T, Petzold C, Keasling J (2014) Metabolic pathway optimization using ribosome binding site variants and combinatorial gene assembly. Appl Microbiol Biotechnol 98(4):1567–1581

    Article  CAS  Google Scholar 

  106. Oliver JWK, Machado IMP, Yoneda H, Atsumi S (2014) Combinatorial optimization of cyanobacterial 2,3-butanediol production. Metab Eng 22:76–82

    Article  CAS  Google Scholar 

  107. Li Y, Gu Q, Lin Z, Wang Z, Chen T, Zhao X (2013) Multiplex iterative plasmid engineering for combinatorial optimization of metabolic pathways and diversification of protein coding sequences. ACS Synth Biol 2(11):651–661

    Article  CAS  Google Scholar 

  108. Zelcbuch L, Antonovsky N, Bar-Even A, Levin-Karp A, Barenholz U, Dayagi M, Liebermeister W, Flamholz A, Noor E, Amram S, Brandis A, Bareia T, Yofe I, Jubran H, Milo R (2013) Spanning high-dimensional expression space using ribosome-binding site combinatorics. Nucleic Acids Res 41(9), e98

    Article  CAS  Google Scholar 

  109. Na D, Lee D (2010) RBSDesigner: software for designing synthetic ribosome binding sites that yields a desired level of protein expression. Bioinformatics 26(20):2633–2634

    Article  CAS  Google Scholar 

  110. Cobb RE, Chao R, Zhao H (2013) Directed evolution: past, present, and future. AIChE J 59(5):1432–1440

    Article  CAS  Google Scholar 

  111. Eriksen DT, Lian J, Zhao H (2014) Protein design for pathway engineering. J Struct Biol 185(2):234–242

    Article  CAS  Google Scholar 

  112. Han L, Liu P, Sun J, Wu Y, Zhang Y, Chen W, Lin J, Wang Q, Ma Y (2015) Engineering catechol 1,2-dioxygenase by design for improving the performance of the cis, cis-muconic acid synthetic pathway in Escherichia coli. Sci Rep 5:13435

    Article  CAS  Google Scholar 

  113. Lewis JC (2015) Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids. Curr Opin Chem Biol 25:27–35

    Article  CAS  Google Scholar 

  114. Neumann H, Neumann-Staubitz P (2010) Synthetic biology approaches in drug discovery and pharmaceutical biotechnology. Appl Microbiol Biotechnol 87(1):75–86

    Article  CAS  Google Scholar 

  115. Neumann H, Slusarczyk AL, Chin JW (2010) De novo generation of mutually orthogonal aminoacyl-tRNA synthetase/tRNA pairs. J Am Chem Soc 132(7):2142–2144

    Article  CAS  Google Scholar 

  116. Ugwumba IN, Ozawa K, Xu Z-Q, Ely F, Foo J-L, Herlt AJ, Coppin C, Brown S, Taylor MC, Ollis DL, Mander LN, Schenk G, Dixon NE, Otting G, Oakeshott JG, Jackson CJ (2011) Improving a natural enzyme activity through incorporation of unnatural amino acids. J Am Chem Soc 133(2):326–333

    Article  CAS  Google Scholar 

  117. Gao L, Du G, Zhou J, Chen J, Liu J (2013) Characterization of a group of pyrroloquinoline quinone-dependent dehydrogenases that are involved in the conversion of L-sorbose to 2-Keto-L-gulonic acid in Ketogulonicigenium vulgare WSH-001. Biotechnol Prog 29(6):1398–1404

    Article  CAS  Google Scholar 

  118. Gao L, Hu Y, Liu J, Du G, Zhou J, Chen J (2014) Stepwise metabolic engineering of Gluconobacter oxydans WSH-003 for the direct production of 2-keto-L-gulonic acid from D-sorbitol. Metab Eng 24:30–37

    Article  CAS  Google Scholar 

  119. Ding M-z, Yan H-f, Li L-f, Zhai F, Shang L-q, Yin Z, Yuan Y-j (2014) Biosynthesis of taxadiene in Saccharomyces cerevisiae: selection of geranylgeranyl diphosphate synthase directed by a computer-aided docking strategy. PLoS One 9(10):e109348

    Google Scholar 

  120. Akhtar MK, Jones PR (2014) Cofactor engineering for enhancing the flux of metabolic pathways. Front Bioeng Biotechnol 2:30

    Article  Google Scholar 

  121. Cui Y-Y, Ling C, Zhang Y-Y, Huang J, Liu J-Z (2014) Production of shikimic acid from Escherichia coli through chemically inducible chromosomal evolution and cofactor metabolic engineering. Microb Cell Fact 13:21

    Article  CAS  Google Scholar 

  122. Lim JH, Seo SW, Kim SY, Jung GY (2013) Model-driven rebalancing of the intracellular redox state for optimization of a heterologous n-butanol pathway in Escherichia coli. Metab Eng 20:56–62

    Article  CAS  Google Scholar 

  123. King ZA, Feist AM (2014) Optimal cofactor swapping can increase the theoretical yield for chemical production in Escherichia coli and Saccharomyces cerevisiae. Metab Eng 24:117–128

    Article  CAS  Google Scholar 

  124. Siu K-H, Chen RP, Sun Q, Chen L, Tsai S-L, Chen W (2015) Synthetic scaffolds for pathway enhancement. Curr Opin Biotechnol 36:98–106

    Article  CAS  Google Scholar 

  125. Dueber JE, Wu GC, Malmirchegini GR, Moon TS, Petzold CJ, Ullal AV, Prather KLJ, Keasling JD (2009) Synthetic protein scaffolds provide modular control over metabolic flux. Nat Biotechnol 27(8):753–759

    Article  CAS  Google Scholar 

  126. Delebecque CJ, Lindner AB, Silver PA, Aldaye FA (2011) Organization of intracellular reactions with rationally designed RNA assemblies. Science 333(6041):470–474

    Article  CAS  Google Scholar 

  127. Conrado RJ, Wu GC, Boock JT, Xu H, Chen SY, Lebar T, Turnšek J, Tomšič N, Avbelj M, Gaber R, Koprivnjak T, Mori J, Glavnik V, Vovk I, Benčina M, Hodnik V, Anderluh G, Dueber JE, Jerala R, DeLisa MP (2012) DNA-guided assembly of biosynthetic pathways promotes improved catalytic efficiency. Nucleic Acids Res 40(4):1879–1889

    Article  CAS  Google Scholar 

  128. Baek J-M, Mazumdar S, Lee S-W, Jung M-Y, Lim J-H, Seo S-W, Jung G-Y, Oh M-K (2013) Butyrate production in engineered Escherichia coli with synthetic scaffolds. Biotechnol Bioeng 110(10):2790–2794

    Article  CAS  Google Scholar 

  129. Avalos JL, Fink GR, Stephanopoulos G (2013) Compartmentalization of metabolic pathways in yeast mitochondria improves the production of branched-chain alcohols. Nat Biotechnol 31(4):335–341

    Article  CAS  Google Scholar 

  130. Herr A, Fischer R (2014) Improvement of Aspergillus nidulans penicillin production by targeting AcvA to peroxisomes. Metab Eng 25:131–139

    Article  CAS  Google Scholar 

  131. Blumhoff ML, Steiger MG, Mattanovich D, Sauer M (2013) Targeting enzymes to the right compartment: metabolic engineering for itaconic acid production by Aspergillus niger. Metab Eng 19:26–32

    Article  CAS  Google Scholar 

  132. Blazeck J, Miller J, Pan A, Gengler J, Holden C, Jamoussi M, Alper H (2014) Metabolic engineering of Saccharomyces cerevisiae for itaconic acid production. Appl Microbiol Biotechnol 98(19):8155–8164

    Article  CAS  Google Scholar 

  133. Bobik TA, Lehman BP, Yeates TO (2015) Bacterial microcompartments: widespread prokaryotic organelles for isolation and optimization of metabolic pathways. Mol Microbiol 98(2):193–207

    Article  CAS  Google Scholar 

  134. Chowdhury C, Sinha S, Chun S, Yeates TO, Bobik TA (2014) Diverse bacterial microcompartment organelles. Microbiol Mol Biol Rev 78(3):438–468

    Article  CAS  Google Scholar 

  135. Lawrence AD, Frank S, Newnham S, Lee MJ, Brown IR, Xue W-F, Rowe ML, Mulvihill DP, Prentice MB, Howard MJ, Warren MJ (2014) Solution structure of a bacterial microcompartment targeting peptide and its application in the construction of an ethanol bioreactor. ACS Synth Biol 3(7):454–465

    Article  CAS  Google Scholar 

  136. Shi L-l, Chen B-n, Gao M, Zhang H-a, Li Y-j, Wang L, Du G-h (2011) The characteristics of therapeutic effect of pinocembrin in transient global brain ischemia/reperfusion rats. Life Sci 88(11–12):521–528

    Google Scholar 

  137. Wu J, Du G, Zhou J, Chen J (2013) Metabolic engineering of Escherichia coli for (2S)-pinocembrin production from glucose by a modular metabolic strategy. Metab Eng 16:48–55

    Article  CAS  Google Scholar 

  138. Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Microbiol 12(5):355–367

    Article  CAS  Google Scholar 

  139. Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD (2015) Complete biosynthesis of opioids in yeast. Science 349(6252):1095–1100

    Article  CAS  Google Scholar 

  140. Tsuruta H, Paddon CJ, Eng D, Lenihan JR, Horning T, Anthony LC, Regentin R, Keasling JD, Renninger NS, Newman JD (2009) High-level production of amorpha-4,11-diene, a precursor of the antimalarial agent artemisinin, in Escherichia coli. PLoS One 4(2), e4489

    Article  CAS  Google Scholar 

  141. Ro D-K, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086):940–943

    Article  CAS  Google Scholar 

  142. Westfall PJ, Pitera DJ, Lenihan JR, Eng D, Woolard FX, Regentin R, Horning T, Tsuruta H, Melis DJ, Owens A, Fickes S, Diola D, Benjamin KR, Keasling JD, Leavell MD, McPhee DJ, Renninger NS, Newman JD, Paddon CJ (2012) Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proc Natl Acad Sci U S A 109(3):E111–E118

    Article  CAS  Google Scholar 

  143. Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A, Main A, Eng D, Polichuk DR, Teoh KH, Reed DW, Treynor T, Lenihan J, Jiang H, Fleck M, Bajad S, Dang G, Dengrove D, Diola D, Dorin G, Ellens KW, Fickes S, Galazzo J, Gaucher SP, Geistlinger T, Henry R, Hepp M, Horning T, Iqbal T, Kizer L, Lieu B, Melis D, Moss N, Regentin R, Secrest S, Tsuruta H, Vazquez R, Westblade LF, Xu L, Yu M, Zhang Y, Zhao L, Lievense J, Covello PS, Keasling JD, Reiling KK, Renninger NS, Newman JD (2013) High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496(7446):528–532

    Article  CAS  Google Scholar 

  144. Dhainaut J, Dlubala A, Guevel R, Medard A, Oddon G, Raymond N, Turconi J (2013) Photochemical process for producing artemisinin. Patent US 8,507,697 B2

    Google Scholar 

  145. Smolke CD, Thodey C, Trenchard I, Galanie S (2014) Benzylisoquinoline alkaloids (bia) producing microbes, and methods of making and using the same. US Patent 20,140,273,109 A1

    Google Scholar 

  146. Enquist-Newman M, Faust AME, Bravo DD, Santos CNS, Raisner RM, Hanel A, Sarvabhowman P, Le C, Regitsky DD, Cooper SR, Peereboom L, Clark A, Martinez Y, Goldsmith J, Cho MY, Donohoue PD, Luo L, Lamberson B, Tamrakar P, Kim EJ, Villari JL, Gill A, Tripathi SA, Karamchedu P, Paredes CJ, Rajgarhia V, Kotlar HK, Bailey RB, Miller DJ, Ohler NL, Swimmer C, Yoshikuni Y (2014) Efficient ethanol production from brown macroalgae sugars by a synthetic yeast platform. Nature 505(7482):239–243

    Article  CAS  Google Scholar 

  147. Lian J, Chao R, Zhao H (2014) Metabolic engineering of a Saccharomyces cerevisiae strain capable of simultaneously utilizing glucose and galactose to produce enantiopure (2R,3R)-butanediol. Metab Eng 23:92–99

    Article  CAS  Google Scholar 

  148. Torella JP, Ford TJ, Kim SN, Chen AM, Way JC, Silver PA (2013) Tailored fatty acid synthesis via dynamic control of fatty acid elongation. Proc Natl Acad Sci U S A 110(28):11290–11295

    Article  CAS  Google Scholar 

  149. de Jong BW, Shi S, Siewers V, Nielsen J (2014) Improved production of fatty acid ethyl esters in Saccharomyces cerevisiae through up-regulation of the ethanol degradation pathway and expression of the heterologous phosphoketolase pathway. Microb Cell Fact 13:39

    Article  CAS  Google Scholar 

  150. Shi S, Valle-Rodriguez J, Khoomrung S, Siewers V, Nielsen J (2012) Functional expression and characterization of five wax ester synthases in Saccharomyces cerevisiae and their utility for biodiesel production. Biotechnol Biofuels 5(1):7

    Article  CAS  Google Scholar 

  151. Shi S, Valle-Rodríguez JO, Siewers V, Nielsen J (2014) Engineering of chromosomal wax ester synthase integrated Saccharomyces cerevisiae mutants for improved biosynthesis of fatty acid ethyl esters. Biotechnol Bioeng 111(9):1740–1747

    Article  CAS  Google Scholar 

  152. Carbonell P, Parutto P, Baudier C, Junot C, Faulon J-L (2014) Retropath: automated pipeline for embedded metabolic circuits. ACS Synth Biol 3(8):565–577

    Article  CAS  Google Scholar 

  153. Chowdhury A, Zomorrodi AR, Maranas CD (2014) k-OptForce: integrating kinetics with flux balance analysis for strain design. PLoS Comput Biol 10(2):e1003487

    Google Scholar 

  154. Ranganathan S, Suthers PF, Maranas CD (2010) OptForce: an optimization procedure for identifying all genetic manipulations leading to targeted overproductions. PLoS Comput Biol 6(4):e1000744

    Google Scholar 

  155. Ebrahim A, Lerman JA, Palsson BO, Hyduke DR (2013) COBRApy: COnstraints-Based Reconstruction and Analysis for python. BMC Syst Biol 7:74

    Article  Google Scholar 

  156. Carbonell P, Parutto P, Herisson J, Pandit SB, Faulon J-L (2014) XTMS: pathway design in an eXTended Metabolic Space. Nucleic Acids Res 42(W1):W389–W394

    Article  CAS  Google Scholar 

  157. McClymont K, Soyer OS (2013) Metabolic tinker: an online tool for guiding the design of synthetic metabolic pathways. Nucleic Acids Res 41(11), e113

    Article  CAS  Google Scholar 

  158. Campodonico MA, Andrews BA, Asenjo JA, Palsson BO, Feist AM (2014) Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path. Metab Eng 25:140–158

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Institutes of Health (GM077596), the National Academies Keck Futures Initiative on Synthetic Biology, the Energy Biosciences Institute, the Department of Energy under Advanced Research Projects Agency-Energy (ARPA-E) (DE-AR0000206), and the National Science Foundation as part of the Center for Enabling New Technologies through Catalysis (CENTC), CHE-0650456 for financial support in our protein and pathway engineering projects.

Author information

Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Eva Garcia-Ruiz, Mohammad HamediRad & Huimin Zhao

  2. Departments of Chemistry, Biochemistry, and Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Huimin Zhao

Authors
  1. Eva Garcia-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad HamediRad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huimin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huimin Zhao .

Editor information

Editors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, Illinois, USA

    Huimin Zhao

  2. Institut für Bioprozess- und Biosystemtechnik, Technische Universitðt Hamburg-Harburg, Hamburg, Germany

    An-Ping Zeng

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Garcia-Ruiz, E., HamediRad, M., Zhao, H. (2016). Pathway Design, Engineering, and Optimization. In: Zhao, H., Zeng, AP. (eds) Synthetic Biology – Metabolic Engineering. Advances in Biochemical Engineering/Biotechnology, vol 162. Springer, Cham. https://doi.org/10.1007/10_2016_12

Download citation

Publish with us

Policies and ethics

Search

Navigation