1932

Abstract

Secondary (specialized) metabolites, produced by bacteria, fungi, plants, and other organisms, exhibit enormous structural variation, and consequently display a wide range of biological activities. Secondary metabolism improves and modulates the phenotype of the host producer. Furthermore, these biological activities have resulted in the use of secondary metabolites in a variety of industrial and pharmaceutical applications. Metabolic engineering presents a powerful strategy to improve access to these valuable molecules. A critical overview of engineering approaches in secondary metabolism is presented, both in heterologous and native hosts. The recognition of the increasing role of compartmentalization in metabolic engineering is highlighted. Engineering approaches to modify the structure of key secondary metabolite classes are also critically evaluated.

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2015-11-23
2024-04-18
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Literature Cited

  1. Aharoni A, Giri AP, Deuerlein S, Griepink F, de Kogel WJ. 1.  et al. 2003. Terpenoid metabolism in wild-type and transgenic Arabidopsis plants. Plant Cell 15:2866–84 [Google Scholar]
  2. Ajikumar PK, Xiao W-H, Tyo KEH, Wang Y, Simeon F. 2.  et al. 2010. Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science 330:70–74 [Google Scholar]
  3. Allen RS, Millgate AG, Chitty JA, Thisleton J, Miller JA. 3.  et al. 2004. RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy. Nat. Biotechnol. 22:1559–66 [Google Scholar]
  4. Anthony JR, Anthony LC, Nowroozi F, Kwon G, Newman JD, Keasling JD. 4.  2009. Optimization of the mevalonate-based isoprenoid biosynthetic pathway in Escherichia coli for production of the anti-malarial drug precursor amorpha-4,11-diene. Metab. Eng. 11:13–19 [Google Scholar]
  5. Ashihara H, Sano H, Crozier A. 5.  2008. Caffeine and related purine alkaloids: biosynthesis, catabolism, function and genetic engineering. Phytochemistry 69:841–56 [Google Scholar]
  6. Avalos JL, Fink GR, Stephanopoulos G. 6.  2013. Compartmentalization of metabolic pathways in yeast mitochondria improves the production of branched-chain alcohols. Nat. Biotechnol. 31:335–41 [Google Scholar]
  7. Bach SS, King BC, Zhan X, Simonsen HT, Hamberger B. 7.  2014. Heterologous stable expression of terpenoid biosynthetic genes using the moss Physcomitrella patens. Methods Mol. Biol. 1153:257–71 [Google Scholar]
  8. Baltz RH. 8.  2011. Strain improvement in actinomycetes in the postgenomic era. J. Ind. Microbiol. Biotechnol. 38:657–66 [Google Scholar]
  9. Bar-Even A, Salah Tawfik D. 9.  2013. Engineering specialized metabolic pathways: Is there a room for enzyme improvements?. Curr. Opin. Biotechnol. 24:310–19 [Google Scholar]
  10. Becker J, Armstrong G, Vandermerwe M, Lambrechts M, Vivier M, Pretorius I. 10.  2003. Metabolic engineering of Saccharomyces cerevisiae for the synthesis of the wine-related antioxidant resveratrol. FEMS Yeast Res. 4:79–85 [Google Scholar]
  11. Bergmann S, Schümann J, Scherlach K, Lange C, Brakhage A, Hertweck C. 11.  2007. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 3:213–17 [Google Scholar]
  12. Bleeker P, Mirabella R, Diergaarde P, VanDoorn A, Tissier A. 12.  et al. 2012. Improved herbivore resistance in cultivated tomato with the sesquiterpene biosynthetic pathway from a wild relative. PNAS 109:20124–29 [Google Scholar]
  13. Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R. 13.  et al. 2013. antiSMASH 2.0: a versatile platform for genome mining of secondary metabolite producers. Nucl. Acids Res. 41:W204–12 [Google Scholar]
  14. Bok JW, Chiang YM, Szewczyk E, Reyes-Dominguez Y, Davidson AD. 14.  et al. 2009. Chromatin-level regulation of biosynthetic gene clusters. Nat. Chem. Biol. 5:462–64 [Google Scholar]
  15. Bok JW, Hoffmeister D, Maggio-Hall LA, Murillo R, Glasner JD, Keller NP. 15.  2006. Genomic mining for Aspergillus natural products. Chem. Biol. 13:31–37 [Google Scholar]
  16. Brown S, Clastre M, Courdavault V, O'Connor SE. 16.  2015. De novo production of the plant-derived alkaloid strictosidine in yeast. PNAS 112:3205–10 [Google Scholar]
  17. Bruce TJ, Aradottir GI, Smart LE, Martin JL, Caulfield JC, Doherty A, Sparks CA, Woodcock CM, Birkett MA, Napier JA, Jones HD, Pickett JA. 17.  2015. The first crop plant genetically engineered to release an insect pheromone for defence. Sci. Rep. 5:11183 [Google Scholar]
  18. Bunet R, Song L, Mendes MV, Corre C, Hotel L. 18.  et al. 2011. Characterization and manipulation of the pathway-specific late regulator AlpW reveals Streptomyces ambofaciens as a new producer of kinamycins. J. Bacteriol. 193:1142–53 [Google Scholar]
  19. Butelli E, Titta L, Giorgio M, Mock HP, Matros A. 19.  et al. 2008. Enrichment of tomato fruit with health-promoting anthocyanins by expression of select transcription factors. Nat. Biotechnol. 26:1301–8 [Google Scholar]
  20. Cacho RA, Tang Y, Chooi YH. 20.  2014. Next-generation sequencing approach for connecting secondary metabolites to biosynthetic gene clusters in fungi. Front. Microbiol. 5:774 [Google Scholar]
  21. Chang MCYE, Eachus RA, Trieu W, Ro D-K, Keasling JD. 21.  2007. Engineering Escherichia coli for production of functionalized terpenoids using plant P450s. Nat. Chem. Biol. 3:274–77 [Google Scholar]
  22. Chemler JA, Lim CG, Daiss JL, Koffas MA. 22.  2010. A versatile microbial system for biosynthesis of novel polyphenols with altered estrogen receptor binding activity. Chem. Biol. 17:392–401 [Google Scholar]
  23. Chen X, Zhou L, Tian K, Kumar A, Singh S. 23.  et al. 2013. Metabolic engineering of Escherichia coli: a sustainable industrial platform for bio-based chemical production. Biotechnol. Adv. 31:1200–23 [Google Scholar]
  24. Chiang Y-M, Lee K-H, Sancheza J, Keller N, Wang C. 24.  2009. Unlocking fungal cryptic natural products. Nat. Prod. Commun. 4:1505–10 [Google Scholar]
  25. Coyle CM, Panaccione DG. 25.  2005. An ergot alkaloid biosynthesis gene and clustered hypothetical genes from Aspergillus fumigatus. Appl. Environ. Microbiol. 71:3112–18 [Google Scholar]
  26. Cummings M, Breitling R, Takano E. 26.  2014. Steps towards the synthetic biology of polyketide biosynthesis. FEMS Microbiol. Lett. 351:116–25 [Google Scholar]
  27. Dai Z, Liu Y, Zhang X, Shi M, Wang B. 27.  et al. 2013. Metabolic engineering of Saccharomyces cerevisiae for production of ginsenosides. Metab. Eng. 20:146–56 [Google Scholar]
  28. Davidovich-Rikanati R, Sitrit Y, Tadmor Y, Iijima Y, Bilenko N. 28.  et al. 2007. Enrichment of tomato flavor by diversion of the early plastidial terpenoid pathway. Nat. Biotechnol. 25:899–901 [Google Scholar]
  29. Davuluri GR, van Tuinen A, Fraser PD, Manfredonia A, Newman R. 29.  et al. 2005. Fruit-specific RNAi-mediated suppression of DET1 enhances carotenoid and flavonoid content in tomatoes. Nat. Biotechnol. 23:890–95 [Google Scholar]
  30. Degenhardt J, Hiltpold I, Kollner TG, Frey M, Gierl A. 30.  et al. 2009. Restoring a maize root signal that attracts insect-killing nematodes to control a major pest. PNAS 106:13213–18 [Google Scholar]
  31. DeLoache WC, Russ ZN, Narcross L, Gonzales AM, Martin VJ, Dueber JE. 31.  2015. An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose. Nat. Chem. Biol. 11:465–71 [Google Scholar]
  32. Dietrich J, Yoshikuni Y, Fisher KJ, Woolard FX, Ockey D. 32.  et al. 2009. A novel semi-biosynthetic route for artemisinin production using engineered substrate-promiscuous P450BM3. ACS Chem. Biol. 4:261–67 [Google Scholar]
  33. Dubock A. 33.  2014. The politics of Golden Rice. GM Crops Food 5:210–22 [Google Scholar]
  34. Duge de Bernonville T, Clastre M, Besseau S, Oudin A, Burlat V. 34.  et al. 2014. Phytochemical genomics of the Madagascar periwinkle: unravelling the last twists of the alkaloid engine. Phytochemistry 113:9–23 [Google Scholar]
  35. Dutta S, Whicher JR, Hansen DA, Hale WA, Chemler JA. 35.  et al. 2014. Structure of a modular polyketide synthase. Nature 510:512–17 [Google Scholar]
  36. Evans BS, Chen Y, Metcalf WW, Zhao H, Kelleher NL. 36.  2011. Directed evolution of the nonribosomal peptide synthetase AdmK generates new andrimid derivatives in vivo. Chem. Biol. 18:601–7 [Google Scholar]
  37. Farhi M, Marhevka E, Ben-Ari J, Algamas-Dimantov A, Liang Z. 37.  et al. 2011. Generation of the potent anti-malarial drug artemisinin in tobacco. Nat. Biotechnol. 29:1072–74 [Google Scholar]
  38. Farhi M, Marhevka E, Masci T, Marcos E, Eyal Y. 38.  et al. 2011. Harnessing yeast subcellular compartments for the production of plant terpenoids. Metab. Eng. 13:474–81 [Google Scholar]
  39. Fischbach MA, Lai JR, Roche ED, Walsh CT, Liu DR. 39.  2007. Directed evolution can rapidly improve the activity of chimeric assembly-line enzymes. PNAS 104:11951–56 [Google Scholar]
  40. Fossati E, Ekins A, Narcross L, Zhu Y, Falgueyret JP. 40.  et al. 2014. Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae. Nat. Commun. 5:3283 [Google Scholar]
  41. Fukushima EO, Seki H, Sawai S, Suzuki M, Ohyama K. 41.  et al. 2013. Combinatorial biosynthesis of legume natural and rare triterpenoids in engineered yeast. Plant Cell Physiol. 54:740–49 [Google Scholar]
  42. Gantt RW, Peltier-Pain P, Thorson JS. 42.  2011. Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules. Nat. Prod. Rep. 28:1811–53 [Google Scholar]
  43. Geu-Flores F, Nielsen MT, Nafisi M, Moldrup ME, Olsen CE. 43.  et al. 2009. Glucosinolate engineering identifies a gamma-glutamyl peptidase. Nat. Chem. Biol. 5:575–77 [Google Scholar]
  44. Gimpel JA, Hyun JS, Schoepp NG, Mayfield SP. 44.  2015. Production of recombinant proteins in microalgae at pilot greenhouse scale. Biotechnol. Bioeng. 112:339–45 [Google Scholar]
  45. Glenn WS, Runguphan W, O'Connor SE. 45.  2013. Recent progress in the metabolic engineering of alkaloids in plant systems. Curr. Opin. Biotechnol. 24:354–65 [Google Scholar]
  46. Gokhale RS, Tsuji SY, Cane DE, Khosla C. 46.  1999. Dissecting and exploiting intermodular communication in polyketide synthases. Science 284:482–85 [Google Scholar]
  47. Gomez-Escribano J, Bibb M. 47.  2011. Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters. Microb. Biotechnol. 4:207–15 [Google Scholar]
  48. Gomez-Escribano JP, Bibb MJ. 48.  2014. Heterologous expression of natural product biosynthetic gene clusters in Streptomyces coelicolor: from genome mining to manipulation of biosynthetic pathways. J. Ind. Microbiol. Biotechnol. 41:425–31 [Google Scholar]
  49. Gottelt M, Kol S, Gomez-Escribano JP, Bibb M, Takano E. 49.  2010. Deletion of a regulatory gene within the cpk gene cluster reveals novel antibacterial activity in Streptomyces coelicolor A3(2). Microbiology 156:2343–53 [Google Scholar]
  50. Guirimand G, Guihur A, Poutrain P, Hericourt F, Mahroug S. 50.  et al. 2011. Spatial organization of the vindoline biosynthetic pathway in Catharanthus roseus. J. Plant Physiol. 168:549–57 [Google Scholar]
  51. Guo F, Xiang S, Li L, Wang B, Rajasarkka J. 51.  et al. 2015. Targeted activation of silent natural product biosynthesis pathways by reporter-guided mutant selection. Metab. Eng. 28C:134–42 [Google Scholar]
  52. Hawkins KM, Smolke CD. 52.  2008. Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae. Nat. Chem. Biol. 4:564–73 [Google Scholar]
  53. Heinig U, Gutensohn M, Dudareva N, Aharoni A. 53.  2013. The challenges of cellular compartmentalization in plant metabolic engineering. Curr. Opin. Biotechnol. 24:239–46 [Google Scholar]
  54. Hofer R, Dong L, Andre F, Ginglinger JF, Lugan R. 54.  et al. 2013. Geraniol hydroxylase and hydroxygeraniol oxidase activities of the CYP76 family of cytochrome P450 enzymes and potential for engineering the early steps of the (seco)iridoid pathway. Metab. Eng. 20:221–32 [Google Scholar]
  55. Hopwood DA, Malpartida F, Kieser HM, Ikeda H, Duncan J. 55.  et al. 1985. Production of “hybrid” antibiotics by genetic engineering. Nature 314:642–44 [Google Scholar]
  56. Hwang EI, Kaneko M, Ohnishi Y, Horinouchi S. 56.  2003. Production of plant-specific flavanones by Escherichia coli containing an artificial gene cluster. Appl. Environ. Microbiol. 69:2699–706 [Google Scholar]
  57. Hwang K, Kim H, Charusanti P, Palsson B, Lee S. 57.  2104. Systems biology and biotechnology of Streptomyces species for the production of secondary metabolites. Biotechnol. Adv. 32:255–68 [Google Scholar]
  58. Ignea C, Pontini M, Maffei ME, Makris AM, Kampranis SC. 58.  2014. Engineering monoterpene production in yeast using a synthetic dominant negative geranyl diphosphate synthase. ACS Synth. Biol. 3:298–306 [Google Scholar]
  59. Ishizaki K, Chiyoda S, Yamato KT, Kohchi T. 59.  2008. Agrobacterium-mediated transformation of the haploid liverwort Marchantia polymorpha L., an emerging model for plant biology. Plant Cell Physiol. 49:1084–91 [Google Scholar]
  60. Jakubczyk D, Caputi L, Hatsch A, Nielsen CAF, Diefenbacher M. 60.  et al. 2015. Discovery and reconstitution of the cycloclavine biosynthetic pathway: enzymatic formation of a cyclopropyl group. Angew. Chem. Int. Ed. 54:5117–21 [Google Scholar]
  61. Jeandet P, Vasserot Y, Chastang T, Courot E. 61.  2013. Engineering microbial cells for the biosynthesis of natural compounds of pharmaceutical significance. BioMed Res. Int. 2013:780145 [Google Scholar]
  62. Jenke-Kodama H, Muller R, Dittmann E. 62.  2008. Evolutionary mechanisms underlying secondary metabolite diversity. Prog. Drug Res. 65:119, 121–40 [Google Scholar]
  63. Jiang H, Wood KV, Morgan JA. 63.  2005. Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Appl. Environ. Microbiol. 71:2962–69 [Google Scholar]
  64. Jiang M, Fang L, Pfeifer BA. 64.  2013. Improved heterologous erythromycin A production through expression plasmid re-design. Biotechnol. Prog. 29:862–69 [Google Scholar]
  65. Jiang M, Pfeifer BA. 65.  2013. Metabolic and pathway engineering to influence native and altered erythromycin production through E. coli. Metab. Eng. 19:42–49 [Google Scholar]
  66. Jiang M, Stephanopoulos G, Pfeifer BA. 66.  2012. Toward biosynthetic design and implementation of Escherichia coli–derived paclitaxel and other heterologous polyisoprene compounds. Appl. Environ. Microbiol. 78:2497–504 [Google Scholar]
  67. Jiang M, Zhang H, Park SH, Li Y, Pfeifer BA. 67.  2013. Deoxysugar pathway interchange for erythromycin analogues heterologously produced through Escherichia coli. Metab. Eng. 20:92–100 [Google Scholar]
  68. Kao CM, Katz L, Khosla C. 68.  1994. Engineered biosynthesis of a complete macrolactone in a heterologous host. Science 265:509–12 [Google Scholar]
  69. Kappers IF, Aharoni A, van Herpen TWJM, Luckerhoff LLP, Dicke M, Bouwmeester HJ. 69.  2005. Genetic engineering of terpenoid metabolism attracts bodyguards to Arabidopsis. Science 309:2070–72 [Google Scholar]
  70. Kapur S, Lowry B, Yuzawa S, Kenthirapalan S, Chen AY. 70.  et al. 2012. Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation. PNAS 109:4110–15 [Google Scholar]
  71. Kennedy J. 71.  2008. Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. Nat. Prod. Rep. 25:25–34 [Google Scholar]
  72. Kirby J, Romanini DW, Paradise EM, Keasling JD. 72.  2008. Engineering triterpene production in Saccharomyces cerevisiae-beta-amyrin synthase from Artemisia annua. FEBS J. 275:1852–59 [Google Scholar]
  73. Kitaoka N, Lu X, Yang B, Peters RJ. 73.  2015. The application of synthetic biology to elucidation of plant mono-, sesqui-, and diterpenoid metabolism. Mol. Plant 8:6–16 [Google Scholar]
  74. Klein J, Heal JR, Hamilton WD, Boussemghoune T, Tange TO. 74.  et al. 2014. Yeast synthetic biology platform generates novel chemical structures as scaffolds for drug discovery. ACS Synth. Biol. 3:314–23 [Google Scholar]
  75. Koopman F, Beekwilder J, Crimi B, van Houwelingen A, Hall R. 75.  et al. 2012. De novo production of the flavonoid naringenin in engineered Saccharomyces cerevisiae. Microb. Cell Fact. 11:155 [Google Scholar]
  76. Krivoruchko A, Nielsen J. 76.  2014. Production of natural products through metabolic engineering of Saccharomyces cerevisiae. Curr. Opin. Biotechnol. 35C:7–15 [Google Scholar]
  77. Kumar S, Hahn FM, Baidoo E, Kahlon TS, Wood DF. 77.  et al. 2012. Remodeling the isoprenoid pathway in tobacco by expressing the cytoplasmic mevalonate pathway in chloroplasts. Metab. Eng. 14:19–28 [Google Scholar]
  78. Kumar V, Jain M. 78.  2015. The CRISPR-Cas system for plant genome editing: advances and opportunities. J. Exp. Bot. 66:47–57 [Google Scholar]
  79. Kunert G, Reinhold C, Gershenzon J. 79.  2010. Constitutive emission of the aphid alarm pheromone, (E)-β-farnesene, from plants does not serve as a direct defense against aphids. BMC Ecol. 10:23 [Google Scholar]
  80. Lange BM, Mahmoud SS, Wildung MR, Turner GW, Davis EM. 80.  et al. 2011. Improving peppermint essential oil yield and composition by metabolic engineering. PNAS 108:16944–49 [Google Scholar]
  81. Laureti L, Song L, Huang S, Corre C, Leblond P. 81.  et al. 2011. Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens. PNAS 108:6258–63 [Google Scholar]
  82. Leonard E, Ajikumar PK, Thayer K, Xiao WH, Mo JD. 82.  et al. 2010. Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control. PNAS 107:13654–59 [Google Scholar]
  83. Li W-H, Vederas J. 83.  2009. Drug discovery and natural products: end of an era or an endless frontier?. Science 325:161–65 [Google Scholar]
  84. Lim CG, Fowler ZL, Hueller T, Schaffer S, Koffas MA. 84.  2011. High-yield resveratrol production in engineered Escherichia coli. Appl. Environ. Microbiol. 77:3451–60 [Google Scholar]
  85. Lim FY, Sanchez JF, Wang CC, Keller NP. 85.  2012. Toward awakening cryptic secondary metabolite gene clusters in filamentous fungi. Methods Enzymol. 517:303–24 [Google Scholar]
  86. Lloyd AM, Walbot V, Davis RW. 86.  1992. Arabidopsis and Nicotiana anthocyanin production activated by maize regulators R and C1. Science 258:1773–75 [Google Scholar]
  87. Lu Y, Rijzaani H, Karcher D, Ruf S, Bock R. 87.  2013. Efficient metabolic pathway engineering in transgenic tobacco and tomato plastids with synthetic multigene operons. PNAS 110:E623–32 [Google Scholar]
  88. Lubertozzi D, Keasling JD. 88.  2009. Developing Aspergillus as a host for heterologous expression. Biotechnol. Adv. 27:53–75 [Google Scholar]
  89. Luo Y, Huang H, Liang J, Wang M, Lu L. 89.  et al. 2013. Activation and characterization of a cryptic polycyclic tetramate macrolactam biosynthetic gene cluster. Nat. Commun. 4:2894 [Google Scholar]
  90. Ma SM, Li JWH, Choi JW, Zhou H, Lee KKM. 90.  et al. 2009. Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326:589–92 [Google Scholar]
  91. Malpartida F, Hopwood DA. 91.  1984. Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature 309:462–64 [Google Scholar]
  92. Martin VJJ, Pitera DJ, Withers ST, Newman JD, Keasling JD. 92.  2003. Engineering the mevalonate pathway in Escherichia coli for production of terpenoids. Nat. Biotechnol. 21:796–802 [Google Scholar]
  93. McCranie EK, Bachmann BO. 93.  2014. Bioactive oligosaccharide natural products. Nat. Prod. Rep. 31:1026–42 [Google Scholar]
  94. McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M. 94.  et al. 1999. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel “unnatural” natural products. PNAS 96:1846–51 [Google Scholar]
  95. McDaniel R, Welch M, Hutchinson CR. 95.  2005. Genetic approaches to polyketide antibiotics. Chem. Rev. 105:543–58 [Google Scholar]
  96. Metlen KL, Aschehoug ET, Callaway RM. 96.  2009. Plant behavioural ecology: dynamic plasticity in secondary metabolites. Plant Cell Environ. 32:641–53 [Google Scholar]
  97. Meyer P, Heidmann I, Forkmann G, Saedler H. 97.  1987. A new petunia flower colour generated by transformation of a mutant with a maize gene. Nature 330:677–78 [Google Scholar]
  98. Miettinen K, Dong L, Navrot N, Schneider T, Burlat V. 98.  et al. 2014. The seco-iridoid pathway from Catharanthus roseus. Nat. Commun. 5:3606 [Google Scholar]
  99. Mikkelsen MD, Olsen CE, Halkier BA. 99.  2010. Production of the cancer-preventive glucoraphanin in tobacco. Mol. Plant 3:751–59 [Google Scholar]
  100. Minami H, Kim JS, Ikezawa N, Takemura T, Katayama T. 100.  et al. 2008. Microbial production of plant benzylisoquinoline alkaloids. PNAS 105:7393–98 [Google Scholar]
  101. Mora-Pale M, Sanchez-Rodriguez SP, Linhardt RJ, Dordick JS, Koffas MA. 101.  2013. Metabolic engineering and in vitro biosynthesis of phytochemicals and non-natural analogues. Plant Sci. 210:10–24 [Google Scholar]
  102. Morrone D, Lowry L, Determan MK, Hershey DM, Xu M, Peters RJ. 102.  2010. Increasing diterpene yield with a modular metabolic engineering system in E. coli: comparison of MEV and MEP isoprenoid precursor pathway engineering. Appl. Microbiol. Biotechnol. 85:1893–906 [Google Scholar]
  103. Moses T, Pollier J, Almagro L, Buyst D, Van Montagu M. 103.  et al. 2014. Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16α hydroxylase from Bupleurum falcatum. PNAS 111:1634–39 [Google Scholar]
  104. Mugford ST, Louveau T, Melton R, Qi X, Bakht S. 104.  et al. 2013. Modularity of plant metabolic gene clusters: a trio of linked genes that are collectively required for acylation of triterpenes in oat. Plant Cell 25:1078–92 [Google Scholar]
  105. Muir SR, Collins GJ, Robinson S, Hughes S, Bovy A. 105.  et al. 2001. Overexpression of petunia chalcone isomerase in tomato results in fruit containing increased levels of flavonols. Nat. Biotechnol. 19:470–74 [Google Scholar]
  106. Murli S, Kennedy J, Dayem LC, Carney JR, Kealey JT. 106.  2003. Metabolic engineering of Escherichia coli for improved 6-deoxyerythronolide B production. J. Ind. Microbiol. Biotechnol. 30:500–9 [Google Scholar]
  107. Naesby M, Nielsen SV, Nielsen CA, Green T, Tange TO. 107.  et al. 2009. Yeast artificial chromosomes employed for random assembly of biosynthetic pathways and production of diverse compounds in Saccharomyces cerevisiae. Microb. Cell Fact. 8:45 [Google Scholar]
  108. Nakagawa A, Minami H, Kim J-S, Koyanagi T, Katayama T. 108.  et al. 2011. A bacterial platform for fermentative production of plant alkaloids. Nat. Commun. 2:326 [Google Scholar]
  109. Nekrasov V, Staskawicz B, Weigel D, Jones JDG, Kamoun S. 109.  2013. Targeted mutagenesis in the model plant Nicotiana benthamiana using Cas9 RNA-guided endonuclease. Nat. Biotechnol. 31:691–93 [Google Scholar]
  110. Newman D, Cragg G. 110.  2012. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75:311–35 [Google Scholar]
  111. Nour-Eldin HH, Andersen TG, Burow M, Madsen SR, Jorgensen ME. 111.  et al. 2012. NRT/PTR transporters are essential for translocation of glucosinolate defence compounds to seeds. Nature 488:531–34 [Google Scholar]
  112. Nour-Eldin HH, Halkier BA. 112.  2013. The emerging field of transport engineering of plant specialized metabolites. Curr. Opin. Biotechnol. 24:263–70 [Google Scholar]
  113. Nutzmann HW, Osbourn A. 113.  2014. Gene clustering in plant specialized metabolism. Curr. Opin. Biotechnol. 26:91–99 [Google Scholar]
  114. Olano C, Garcia I, Gonzalez A, Rodriguez M, Rozas D. 114.  et al. 2014. Activation and identification of five clusters for secondary metabolites in Streptomyces albus J1074. Microb. Biotechnol. 7:242–56 [Google Scholar]
  115. Oman TJ, Knerr PJ, Bindman NA, Velasquez JE, van der Donk WA. 115.  2012. An engineered lantibiotic synthetase that does not require a leader peptide on its substrate. J. Am. Chem. Soc. 134:6952–55 [Google Scholar]
  116. Paddon CJ, Keasling JD. 116.  2014. Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat. Rev. Microbiol. 12:355–67 [Google Scholar]
  117. Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K. 117.  et al. 2013. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496:528–32 [Google Scholar]
  118. Patton GC, van der Donk WA. 118.  2005. New developments in lantibiotic biosynthesis and mode of action. Curr. Opin. Microbiol. 8:543–51 [Google Scholar]
  119. Peiru S, Menzella HG, Rodriguez E, Carney J, Gramajo H. 119.  2005. Production of the potent antibacterial polyketide erythromycin C in Escherichia coli. Appl. Environ. Microbiol. 71:2539–47 [Google Scholar]
  120. Pfeifer B, Admiraal S, Gramajo H, Cane D, Khosla C. 120.  2001. Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science 291:1790–92 [Google Scholar]
  121. Pickens LB, Tang Y, Chooi YH. 121.  2011. Metabolic engineering for the production of natural products. Annu. Rev. Chem. Biomol. Eng. 2:211–36 [Google Scholar]
  122. Putignani L, Massa O, Alisi A. 122.  2013. Engineered Escherichia coli as new source of flavonoids and terpenoids. Food Res. Int. 54:1084–95 [Google Scholar]
  123. Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL. 123.  et al. 2006. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–43 [Google Scholar]
  124. Roy A, Gruschow S, Cairns N, Goss R. 124.  2010. Gene expression enabling synthetic diversification of natural products: chemogenetic generation of pacidamycin analogs. J. Am. Chem. Soc. 132:12243–45 [Google Scholar]
  125. Rudd BAM, Hopwood DA. 125.  1980. A pigmented mycelial antibiotic in Streptomyces coelicolor: control by a chromosomal gene cluster. J. Gen. Microbiol. 119:333–40 [Google Scholar]
  126. Rugbjerg P, Naesby M, Mortensen UH, Frandsen RJ. 126.  2013. Reconstruction of the biosynthetic pathway for the core fungal polyketide scaffold rubrofusarin in Saccharomyces cerevisiae. Microb. Cell Fact. 12:31 [Google Scholar]
  127. Runguphan W, Maresh JJ, O'Connor SE. 127.  2009. Silencing of tryptamine biosynthesis for production of nonnatural alkaloids in plant culture. PNAS 106:13673–78 [Google Scholar]
  128. Runguphan W, Qu X, O'Connor SE. 128.  2010. Integrating carbon-halogen bond formation into medicinal plant metabolism. Nature 468:461–64 [Google Scholar]
  129. Ryan KL, Moore CT, Panaccione DG. 129.  2013. Partial reconstruction of the ergot alkaloid pathway by heterologous gene expression in Aspergillus nidulans. Toxins 5:445–55 [Google Scholar]
  130. Sainsbury F, Saxena P, Geisler K, Osbourn A, Lomonossoff GP. 130.  2012. Using a virus-derived system to manipulate plant natural product biosynthetic pathways. Methods Enzmol. 517:185–202 [Google Scholar]
  131. Santos CN, Koffas M, Stephanopoulos G. 131.  2011. Optimization of a heterologous pathway for the production of flavonoids from glucose. Metab. Eng. 13:392–400 [Google Scholar]
  132. Schilmiller AL, Pichersky E, Last RL. 132.  2012. Taming the hydra of specialized metabolism: how systems biology and comparative approaches are revolutionizing plant biochemistry. Curr. Opin. Plant Biol. 15:338–44 [Google Scholar]
  133. Shi Y, Yang X, Garg N, van der Donk WA. 133.  2011. Production of lantipeptides in Escherichia coli. J. Am. Chem. Soc. 133:2338–41 [Google Scholar]
  134. Shier W, Rinehart K, Gottlieb D. 134.  1969. Preparation of four new antibiotics from a mutant of Streptomyces fradiae. PNAS 63:198–204 [Google Scholar]
  135. Siddiqui MS, Thodey K, Trenchard I, Smolke CD. 135.  2012. Advancing secondary metabolite biosynthesis in yeast with synthetic biology tools. FEMS Yeast Res. 12:144–70 [Google Scholar]
  136. Takahashi S, Yeo Y, Greenhagen B, McMullin T, Song L. 136.  et al. 2007. Metabolic engineering of sesquiterpene metabolism in yeast. Biotechnol. Bioeng. 97:170–81 [Google Scholar]
  137. Thodey K, Galanie S, Smolke CD. 137.  2014. A microbial biomanufacturing platform for natural and semisynthetic opioids. Nat. Chem. Biol. 10:837–44 [Google Scholar]
  138. Ting HM, Wang B, Ryden AM, Woittiez L, van Herpen T. 138.  et al. 2013. The metabolite chemotype of Nicotiana benthamiana transiently expressing artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and relative gene dosage. New Phytol. 199:352–66 [Google Scholar]
  139. Trantas E, Panopoulos N, Ververidis F. 139.  2009. Metabolic engineering of the complete pathway leading to heterologous biosynthesis of various flavonoids and stilbenoids in Saccharomyces cerevisiae. Metab. Eng. 11:355–66 [Google Scholar]
  140. Trantas EA, Koffas MA, Xu P, Ververidis F. 140.  2015. When plants produce not enough or at all: metabolic engineering of flavonoids in microbial hosts. Front. Plant Sci. 6:7 [Google Scholar]
  141. van Dijl JM, Hecker M. 141.  2013. Bacillus subtilis: from soil bacterium to super-secreting cell factory. Microb. Cell Fact. 12:3 [Google Scholar]
  142. Van Moerkercke A, Steensma P, Schweizer F, Pollier J, Gariboldi I. 142.  et al. 2015. The bHLH transcription factor BIS1 controls the iridoid branch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus. PNAS 112:8130–35 [Google Scholar]
  143. Vogt T. 143.  2010. Phenylpropanoid biosynthesis. Mol. Plant 3:2–20 [Google Scholar]
  144. Walker MC, Thuronyi BW, Charkoudian LK, Lowry B, Khosla C, Chang MC. 144.  2013. Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways. Science 341:1089–94 [Google Scholar]
  145. Wang Y, Pfeifer BA. 145.  2008. 6-Deoxyerythronolide B production through chromosomal localization of the deoxyerythronolide B synthase genes in E. coli. Metab. Eng. 10:33–38 [Google Scholar]
  146. Wenzel SC, Muller R. 146.  2005. Formation of novel secondary metabolites by bacterial multimodular assembly lines: deviations from textbook biosynthetic logic. Curr. Opin. Chem. Biol. 9:447–58 [Google Scholar]
  147. Westfall PJ, Pitera DJ, Lenihan JR, Eng D, Woolard FX. 147.  et al. 2012. Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. PNAS 109:E111–18 [Google Scholar]
  148. Winter JM, Tang Y. 148.  2012. Synthetic biological approaches to natural product biosynthesis. Curr. Opin. Biotechnol. 23:736–43 [Google Scholar]
  149. Wong FT, Khosla C. 149.  2012. Combinatorial biosynthesis of polyketides: a perspective. Curr. Opin. Chem. Biol. 16:117–23 [Google Scholar]
  150. Wu S, Jiang Z, Kempinski C, Eric Nybo S, Husodo S. 150.  et al. 2012. Engineering triterpene metabolism in tobacco. Planta 236:867–77 [Google Scholar]
  151. Wu S, Schalk M, Clark A, Miles RB, Coates R, Chappell J. 151.  2006. Redirection of cytosolic or plastidic isoprenoid precursors elevates terpene production in plants. Nat. Biotechnol. 24:1441–47 [Google Scholar]
  152. Xu W, Gavia DJ, Tang Y. 152.  2014. Biosynthesis of fungal indole alkaloids. Nat. Prod. Rep. 31:1474–87 [Google Scholar]
  153. Xu Y, Zhou T, Zhang S, Espinosa-Artiles P, Wang L. 153.  et al. 2014. Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases. PNAS 111:12354–59 [Google Scholar]
  154. Yadav VG, De Mey M, Giaw Lim C, Ajikumar PK, Stephanopoulos G. 154.  2012. The future of metabolic engineering and synthetic biology: towards a systematic practice. Metab. Eng. 14:233–41 [Google Scholar]
  155. Yin WB, Chooi YH, Smith AR, Cacho RA, Hu Y. 155.  et al. 2013. Discovery of cryptic polyketide metabolites from dermatophytes using heterologous expression in Aspergillus nidulans. ACS Synth. Biol. 2:629–34 [Google Scholar]
  156. Yonekura-Sakakibara K, Saito K. 156.  2013. Transcriptome coexpression analysis using ATTED-II for integrated transcriptomic/metabolomic analysis. Methods Mol. Biol. 1011:317–26 [Google Scholar]
  157. Yuan L, Grotewold E. 157.  2015. Metabolic engineering to enhance the value of plants as green factories. Metab. Eng. 27:83–91 [Google Scholar]
  158. Zhang C, Griffith BR, Fu Q, Albermann C, Fu X. 158.  et al. 2006. Exploiting the reversibility of natural product glycosyltransferase-catalyzed reactions. Science 313:1291–94 [Google Scholar]
  159. Zhang H, Wang Y, Wu J, Skalina K, Pfeifer BA. 159.  2010. Complete biosynthesis of erythromycin A and designed analogs using E. coli as a heterologous host. Chem. Biol. 17:1232–40 [Google Scholar]
  160. Zhang L, Ding R, Chai Y, Bonfill M, Moyano E. 160.  et al. 2004. Engineering tropane biosynthetic pathway in Hyoscyamus niger hairy root cultures. PNAS 101:6786–91 [Google Scholar]
  161. Zhou H, Qiao K, Gao Z, Vederas JC, Tang Y. 161.  2010. Insights into radicicol biosynthesis via heterologous synthesis of intermediates and analogs. J. Biol. Chem. 285:41412–21 [Google Scholar]
  162. Zhou K, Qiao K, Edgar S, Stephanopoulos G. 162.  2015. Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nat. Biotechnol. 33:377–83 [Google Scholar]
  163. Ziegler J, Facchini PJ. 163.  2008. Alkaloid biosynthesis: metabolism and trafficking. Annu. Rev. Plant Biol. 59:735–69 [Google Scholar]
  164. Zuker A, Tzfira T, Ben-Meir H, Ovadis M, Shklarman E. 164.  et al. 2002. Modification of flower color and fragrance by antisense suppression of the flavanone 3-hydroxylase gene. Mol. Breed. 9:33–41 [Google Scholar]
  165. Zvi MM, Shklarman E, Masci T, Kalev H, Debener T. 165.  et al. 2012. PAP1 transcription factor enhances production of phenylpropanoid and terpenoid scent compounds in rose flowers. New Phytol. 195:335–45 [Google Scholar]
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