When plants produce not enough or at all: Metabolic engineering of flavonoids in microbial hosts

Frontiers in Plant Science

Volumn 6, Issue JAN, 2015, Pages 1-16

  Trantas, Emmanouil A ^a   Koffas, Mattheos A G ^b   Xu, Peng ^c   Ververidis, Filippos ^a  

^a TECHNOLOGICAL EDUCATIONAL INSTITUTE OF CRETE   (Greece)

^b RENSSELAER POLYTECHNIC INSTITUTE   (United States)

^c Massachusetts Institute of Technology Cambridge   (United States)

Author keywords

Combinatorial biosynthesi; Dynamic regulation; Flavonoid biosynthesis; Metabolic control; Metabolic engineering; Secondary metabolites; Unnatural flavonoids

Indexed keywords

EID: 84922212497     PISSN: None     EISSN: 1664462X     Source Type: Journal    
DOI: 10.3389/fpls.2015.00007     Document Type: Article

References (108)

1. Abdullah, M. A., Rahmah, A., Sinskey, A. J., and Rha, C. K. (2008). Cell engineering and molecular pharming for biopharmaceuticals. Open Med. Chem. J. 2, 49-61. doi: 10.2174/1874104500802010049
2. Afroz, T., and Beisel, C. L. (2013). Understanding and exploiting feedback in synthetic biology. Chem. Eng. Sci. 103, 79-90. doi: 10.1016/j.ces.2013.02.017
3. Akashi, T., Aoki, T., and Ayabe, S. (1999). Cloning and functional expression of a cytochrome P450 cDNA encoding 2-hydroxyisoflavanone synthase involved in biosynthesis ofthe isoflavonoid skeleton in licorice. Plant Physiol. 121, 821-828. doi: 10.1104/pp.121.3.821
4. Altschul, S. F., Gish, W., Miller, W., Myers, E. W., and Lipman, D. J. (1990). Basic local alignment search tool. J. Mol. Biol. 215, 403-410. doi: 10.1016/S0022-2836(05)80360-2
5. Andersen, O. M., and Markham, K. R. (2006). Flavonoids: Chemistry, Biochemistry, and Applications. Boca Raton, FL: CRC, Taylor & Francis.
6. Bakke, P., Carney, N., Deloache, W., Gearing, M., Ingvorsen, K., Lotz, M., et al. (2009). Evaluation of three automated genome annotations for Halorhabdus utahensis. PLoS ONE 4:e6291. doi: 10.1371/journal.pone.0006291
7. Bennett, R. N., and Wallsgrove, R. M. (1994). Secondary metabolites in plant defence mechanisms. New Phytol. 127, 617-633. doi: 10.1111/j.1469-8137.1994.tb02968.x
8. Bhagwat, S., Haytowitz, D. B., and Holden, J. M. (2014). USDA Database for the Flavonoid Contentof Selected Foods, Release 3.1. Beltsville, MD: U.S. Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Nutrient Data Laboratory.
9. Bhan, N., Li, L., Cai, C., Xu, P., Linhardt, R. J., and Koffas, M. A. G. (2014). Enzymatic formation of a resorcylic acid by creating a structure-guided singlepoint mutation in stilbene synthase. Protein Sci. doi: 10.1002/pro.2600. [Epub ahead of print].
10. Bhan, N., Xu, P., Khalidi, O., and Koffas, M. A. (2013). Redirecting carbon flux into malonyl-CoA to improve resveratrol titers: proof of concept for genetic interventions predicted byOptForce computational framework. Chem. Eng. Sci. 103, 109-114. doi: 10.1016/j.ces.2012.10.009
11. Bulter, T., Lee, S. G., Wong, W. W., Fung, E., Connor, M. R., and Liao, J. C. (2004). Design of artificial cell-cell communication using gene and metabolic networks. Proc. Natl. Acad. Sci. U.S.A. 101, 2299-2304. doi: 10.1073/pnas.0306484101
12. Chemler, J. A., Yan, Y., Leonard, E., and Koffas, M. A. (2007). Combinatorial muta-synthesis of flavonoid analogues from acrylic acids in microorganisms. Org. Lett. 9, 1855-1858. doi: 10.1021/ol0703736
13. Chen, J., Dong, X., Li, Q., Zhou, X., Gao, S., Chen, R., et al. (2013). Biosynthesis of the active compounds of Isatis indigotica based on transcriptome sequencing and metabolites profiling. BMC Genomics 14:857. doi: 10.1186/1471-216414-857
14. Choi, S., Ryu, M., Yoon, Y., Kim, D.-M., and Lee, E. (2012). Glycosylation ofvarious flavonoids byrecombinant oleandomycin glycosyltransferase from Streptomyces antibioticus in batch and repeated batch modes. Biotechnol. Lett. 34, 499-505. doi: 10.1007/s10529-011-0789-z
15. Cress, B. F., Linhardt, R. J., and Koffas, M. A. (2013). “Isoflavonoid production by genetically engineered microorganisms,” in Natural Products, eds K. G. Ramawat and J. M. Merillon (Berlin; Heidelberg: Springer-Verlag).
16. Crosby, K. C., Pietraszewska-Bogiel, A., Gadella, T. W. J. Jr, and Winkel, B. S. J.. Forster resonance energy transfer demonstrates a flavonoid metabolon in living plant cells that displays competitive interactions between enzymes. FEBSLett. 585, 2193-2198. doi: 10.1016/j.febslet.2011.05.066
17. Dahl, R. H., Zhang, F., Alonso-Gutierrez, J., Baidoo, E., Batth, T. S., Redding-Johanson, A. M., et al. (2013). Engineering dynamic pathway regulation using stress-response promoters. Nat. Biotechnol. 31, 1039-1046. doi: 10.1038/nbt.2689
18. Demain, A. L., and Fang, A. (2000). The natural functions of secondary metabolites. Adv. Biochem. Eng. Biotechnol. 69, 1-39. doi: 10.1007/3-540-44964-7_1
19. Dixon, R. A., and Paiva, N. L. (1995). Stress-induced phenylpropanoid metabolism. PlantCell 7, 1085-1097. doi: 10.1105/tpc.7.7.1085
20. Dixon, R. A., and Steele, C. L. (1999). Flavonoids and isoflavonoids-a gold mine for metabolic engineering. Trends Plant Sci. 4, 394-400. doi: 10.1016/S1360-1385(99)01471-5
21. Farmer, W. R., and Liao, J. C. (2000). Improving lycopene production in Escherichia coli by engineering metabolic control. Nat. Biotechnol. 18, 533-537. doi: 10.1038/75398
22. Felnagle, E. A., Chaubey, A., Noey, E. L., Houk, K. N., and Liao, J. C. (2000). Engineering synthetic recursive pathways to generate non-natural small molecules. Nat. Chem. Biol. 8, 518-526. doi: 10.1038/nchembio.959
23. Firn, R. D., and Jones, C. G. (2000). The evolution of secondary metabolism-a unifying model. Mol. Microbiol. 37, 989-994. doi: 10.1046/j.1365-2958.2000.02098.x
24. Forbes, A. M., Lin, H., Meadows, G. G., and Meier, G. P. (2014). Synthesis and anticancer activity of new flavonoid analogs and inconsistencies in assays related to proliferation and viability measurements. Int. J. Oncol. 45, 831-842. doi: 10.3892/ijo.2014.2452
25. Fowler, Z. L., Baron, C. M., Panepinto, J. C., and Koffas, M. A. (2011). Melanization of flavonoids by fungal and bacterial laccases. Yeast 28, 181-188. doi: 10.1002/yea.1829
26. Fukushima, E. O., Seki, H., Sawai, S., Suzuki, M., Ohyama, K., Saito, K., et al. (2013). Combinatorial biosynthesis of legume natural and rare triterpenoids in engineered yeast. Plant Cell Physiol. 54, 740-749. doi: 10.1093/pcp/pct015
27. Fung, E., Wong, W. W., Suen, J. K., Bulter, T., Lee, S. G., and Liao, J. C. (2005). A synthetic gene-metabolic oscillator. Nature 435, 118-122. doi: 10.1038/nature03508
28. Gholami, A., De Geyter, N., Pollier, J., Goormachtig, S., and Goossens, A. (2014). Natural product biosynthesis in Medicago species. Nat. Prod. Rep. 31, 356-380. doi: 10.1039/c3np70104b
29. Gurung, S. K., Kim, S. B., and Park, H. (2010). Synthesis and characterization of novel unnatural bichalcones. Arch. Pharm. Res. 33, 1919-1926. doi: 10.1007/s12272-010-1205-2
30. Harborne, J. B., and Williams, C. A. (2000). Advances in flavonoid research since 1992. Phytochemistry 55, 481-504. doi: 10.1016/S0031-9422(00)00235-1
31. Haslam, E. (1995). Secondary metabolism-evolution and function: products or processes? Chemoecology 5-6, 89-95. doi: 10.1007/BF01259437
32. He, X. Z., Li, W. S., Blount, J. W., and Dixon, R. A. (2008). Regioselective synthesis of plant (iso)flavone glycosides in Escherichia coli. Appl. Microbiol. Biotechnol. 80, 253-260. doi: 10.1007/s00253-008-1554-7
33. Holton, T. A., Brugliera, F., and Tanaka, Y. (1993). Cloning and expression of flavonol synthase from Petunia hybrida. Plant J. 4, 1003-1010. doi: 10.1046/j.1365-313X.1993.04061003.x
34. Holtz, W. J., and Keasling, J. D. (2010). Engineering static and dynamic control of synthetic pathways. Cell 140, 19-23. doi: 10.1016/j.cell.2009.12.029
35. Hui, P. (2014). Next generation sequencing: chemistry, technology and applications. Top. Curr. Chem. 336, 1-18. doi: 10.1007/128_2012_329
36. Jenke-Kodama, H., Muller, R., and Dittmann, E. (2008). “Evolutionary mechanisms underlying secondary metabolite diversity,” in Natural Compounds as Drugs, Vol. 1, eds F. Petersen and R. Amstutz (Basel: Springer), 119-140.
37. Joe, E., Kim, B.-G., An, B.-C., Chong, Y., and Ahn, J.-H. (2010). Engineering of flavonoid O-methyltransferase for a novel regioselectivity. Mol. Cells 30, 137-141. doi: 10.1007/s10059-010-0098-8
38. Katsuyama, Y., Funa, N., Miyahisa, I., and Horinouchi, S. (2007a). Synthesis of unnatural flavonoids and stilbenes by exploiting the plant biosynthetic pathway in Escherichia coli. Chem. Biol. 14, 613-621. doi: 10.1016/j.chembiol.2007.05.004
39. Katsuyama, Y., Miyahisa, I., Funa, N., and Horinouchi, S. (2007b). One-pot synthesis of genistein from tyrosine by coincubation of genetically engineered Escherichia coli and Saccharomyces cerevisiae cells Appl. Microbiol. Biotechnol. 73, 1143-1149. doi: 10.1007/s00253-006-0568-2
40. Kim, B. G., Joe, E. J., and Ahn, J. H. (2010). Molecular characterization of flavonol synthase from poplar and its application to the synthesis of 3-O-methylkaempferol. Biotechnol. Lett. 32, 579-584. doi: 10.1007/s10529-009-0188-x
41. Kim, B. G., Kim, H. J., and Ahn, J. H. (2012b). Production of bioactive flavonol rhamnosides by expression of plant genes in Escherichia coli. J. Agric. Food Chem. 60, 11143-11148. doi: 10.1021/jf302123c
42. Kim, B.-G., Sung, S. H., and Ahn, J.-H. (2012a). Biological synthesis of quercetin 3-ON-acetylglucosamine conjugate using engineered Escherichia coli expressing UGT78D2. Appl. Microbiol. Biotechnol. 93, 2447-2453. doi: 10.1007/s00253-011-3747-8
43. Kim, D. H., Kim, B.-G., Jung, N. R., and Ahn, J.-H. (2009). Production of genistein from naringenin using Escherichia coli containing isoflavone synthase-cytochrome P450 reductase fusion protein. J. Microbiol. Biotechnol. 19, 1612-1616. doi: 10.4014/jmb.0905.05043
44. Kim, H., Kim, B.-G., and Ahn, J.-H. (2013a). Regioselective synthesis of flavonoid bisglycosides using Escherichia coli harboring two glycosyltrans-ferases. Appl. Microbiol. Biotechnol. 97, 5275-5282. doi: 10.1007/s00253-013-4844-7
45. Kim, J. H., Shin, K. H., Ko, J. H., and Ahn, J. H. (2006). Glucosylation of flavonols by Escherichia coli expressing glucosyltransferase from rice (Oryza sativa). J. Biosci. Bioeng. 102, 135-137. doi: 10.1263/jbb.102.135
46. Kim, M. J., Kim, B. G., and Ahn, J. H. (2013b). Biosynthesis of bioactive methylated flavonoids in Escherichia coli. Appl. Microbiol. Biotechnol. 97, 7195-7204. doi: 10.1007/s00253-013-5020-9
47. Koopman, F., Beekwilder, J., Crimi, B., Houwelingen, A., Hall, R., Bosch, D., et al. (2012). De novo production of the flavonoid naringenin in engineered Saccharomyces cerevisiae. Microb. Cell Fact. 11, 155. doi: 10.1186/1475-285911-155
48. Lan, E. I., and Liao, J. C. (2012). ATP drives direct photosynthetic production ofbutanol in cyanobacteria. Proc. Natl. Acad. Sci. U.S.A. 109, 6018-6023. doi: 10.1073/pnas.1200074109
49. Lee, H., Kim, B.-G., and Ahn, J.-H. (2014). Production of bioactive hydroxyflavones by using monooxygenase from Saccharothrix espanaensis. J. Biotechnol. 176, 11-17. doi: 10.1016/j.jbiotec.2014.02.002
50. Leonard, E., and Koffas, M. A. G. (2007). Engineering of artificial plant cytochrome P450 enzymes for synthesis of isoflavones by Escherichia coli. Appl. Environ. Microbiol. 73, 7246-7251. doi: 10.1128/aem.01411-07
51. Leonard, E., Lim, K. H., Saw, P. N., and Koffas, M. A. (2007). Engineering central metabolic pathways for high-level flavonoid production in Escherichia coli. Appl. Environ. Microbiol. 73, 3877-3886. doi: 10.1128/AEM.00200-07
52. Leonard, E., Runguphan, W., O’Connor, S., and Prather, K. J. (2009). Opportunities in metabolic engineering to facilitate scalable alkaloid production. Nat. Chem. Biol. 5,292-300. doi: 10.1038/nchembio.160
53. Leonard, E., Yan, Y., and Koffas, M. A. G. (2006). Functional expression of a P450 flavonoid hydroxylase for the biosynthesis of plant-specific hydroxylated flavonols in Escherichia coli. Metab. Eng. 8, 172-181. doi: 10.1016/j.ymben.2005.11.001
54. Li, J., Li, Z., Li, C., Gou, J., and Zhang, Y. (2014). Molecular cloning and characterization of an isoflavone 7-O-glucosyltransferase from Pueraria lobata. Plant Cell Rep. 33, 1173-1185. doi: 10.1007/s00299-014-1606-7
55. Lukacin, R., Wellmann, F., Britsch, L., Martens, S., and Matern, U. (2003). Flavonol synthase from Citrus unshiu is a bifunctional dioxygenase. Phytochemistry 62, 287-292. doi: 10.1016/S0031-9422(02)00567-8
56. Malla, S., Koffas, M. A. G., Kazlauskas, R. J., and Kim, B. G. (2012). Production of 7-O-methyl aromadendrin, amedicinallyvaluable flavonoid, in Escherichia coli. Appl. Environ. Microbiol. 78, 684-694. doi: 10.1128/AEM.06274-11
57. Malla, S., Pandey, R. P., Kim, B. G., and Sohng, J. K. (2013). Regiospecific modifications of naringenin for astragalin production in Escherichia coli. Biotechnol. Bioeng. 110, 2525-2535. doi: 10.1002/bit.24919
58. Marienhagen, J., and Bott, M. (2013). Metabolic engineering of microorganisms for the synthesis of plant natural products. J. Biotechnol. 163, 166-178. doi: 10.1016/j.jbiotec.2012.06.001
59. Martens, S., Forkmann, G., Britsch, L., Wellmann, F., Matern, U., and Lukacin, R. (2003). Divergent evolution of flavonoid 2-oxoglutarate-dependent dioxygenases in parsley. FEBSLett. 544, 93-98. doi: 10.1016/S0014-5793(03)00479-4
60. Miyahisa, I., Funa, N., Ohnishi, Y., Martens, S., Moriguchi, T., and Horinouchi, S. (2006). Combinatorial biosynthesis of flavones and flavonols in Escherichia coli. Appl. Microbiol. Biotechnol. 71, 53-58. doi: 10.1007/s00253-005-0116-5
61. Mora-Pale, M., Sanchez-Rodriguez, S. P., Linhardt, R. J., Dordick, J. S., and Koffas, M. A. G. (2013). Metabolic engineering and in vitro biosynthesis of phytochemicals and non-natural analogues. Plant Sci. 210, 10-24. doi: 10.1016/j.plantsci.2013.05.005
62. Mora-Pale, M., Sanchez-Rodriguez, S. P., Linhardt, R. J., Dordick, J. S., and Koffas, M. A. G. (2014). Biochemical strategies for enhancing the in vivo production of natural products with pharmaceutical potential. Curr. Opin. Biotechnol. 25, 86-94. doi: 10.1016/j.copbio.2013.09.009
63. Morozova, O., and Marra, M. A. (2008). Applications of next-generation sequencing technologies in functional genomics. Genomics 92, 255-264. doi: 10.1016/j.ygeno.2008.07.001
64. Mu, L., He, J.-J., Pan, Q.-H., He, F., and Duan, C.-Q. (2014). Tissue-specific accumulation of flavonoids in grape berries is related to transcriptional expression of VvF3'H and VvF3'5'H. S. Afr. J. Enol. Vitic. 35.
65. Naesby, M., Nielsen, S. V., Nielsen, C. A., Green, T., Tange, T. O., Simon, E., 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. doi: 10.1186/1475-2859-8-45
66. Nagashima, S., Inagaki, R., Kubo, A., Hirotani, M., and Yoshikawa, T. (2004). cDNA cloning and expression of isoflavonoid-specific glucosyltransferase from Glycyrrhiza echinata cell-suspension cultures. Planta 218, 456-459. doi: 10.1007/s00425-003-1118-0
67. Nguyen, T. B., Lozach, O., Surpateanu, G., Wang, Q., Retailleau, P., Iorga, B. I., et al. (2012). Synthesis, biological evaluation, and molecular modeling of natural and unnatural flavonoidal alkaloids, inhibitors of kinases. J. Med. Chem. 55, 2811-2819. doi: 10.1021/jm201727w
68. Noel, J. P., Austin, M. B., and Bomati, E. K. (2005). Structure-function relationships in plant phenylpropanoid biosynthesis. Curr. Opin. Plant Biol. 8, 249-253. doi: 10.1016/j.pbi.2005.03.013
69. Otero, J. M., and Nielsen, J. (2010). Industrial systems biology. Biotechnol. Bioeng. 105,439-460. doi: 10.1002/bit.22592
70. Pandey, B. P., Lee, N., Choi, K. Y., Jung, E., Jeong, D. H., and Kim, B. G. (2013). Screening of bacterial cytochrome P450s responsible for regiospecific hydroxylation of (iso)flavonoids. Enzyme Microb. Technol. 48, 386-392. doi: 10.1016/j.enzmictec.2011.01.001
71. Pandey, R. P., Malla, S., Simkhada, D., Kim, B. G., and Sohng, J. K. (2013). Production of 3-O-xylosyl quercetin in Escherichia coli. Appl. Microbiol. Biotechnol. 97, 1889-1901. doi: 10.1007/s00253-012-4438-9
72. Pandey, R. P., Parajuli, P., Koirala, N., Lee, J. H., Park, Y. I., and Sohng, J. K. (2013). Glucosylation of isoflavonoids in engineered Escherichia coli. Mol. Cells 37, 172-177. doi: 10.14348/molcells.2014.2348
73. Pollier, J., Moses, T., and Goossens, A. (2011). Combinatorial biosynthesis in plants: a (p) review on its potential and future exploitation. Nat. Prod. Rep. 28, 1897-1916. doi: 10.1039/c1np00049g
74. Prosser, G. A., Larrouy-Maumus, G., and Carvalho, L. P. S. (2014). Metabolomic strategies for the identification of new enzyme functions and metabolic pathways. EMBO Rep. 15, 657-669. doi: 10.15252/embr.201338283
75. Rausher, M. D. (2006). “The evolution of flavonoids and their genes," in The Science of Flavonoids, ed E. Grotewold (New York, NY: Springer), 175-211.
76. Reynaud, J., Guilet, D., Terreux, R., Lussignol, M., and Walchshofer, N. (2005). Isoflavonoids in non-leguminous families: an update. Nat. Prod. Rep. 22, 504-515. doi: 10.1039/b416248j
77. Roh, C. (2013). Biotransformation of isoflavone using enzymatic reactions. Molecules 18, 3028-3040. doi: 10.3390/molecules18033028
78. Rothwell, J. A., Perez-Jimenez, J., Neveu, V., Medina-Remon, A., M’hiri, N., Garcia-Lobato, P., et al. (2013). Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content. Database(oxford) 2013:bat070. doi: 10.1093/database/bat070
79. Ruby, Santosh Kumar, R. J, Vishwakarma, R. K, Singh, S, and Khan, B. M. (2014). Molecular cloning and characterization of genistein 4;-O-glucoside specific gly-cosyltransferase from Bacopa monniera. Mol. Biol. Rep. 41, 4675-4688. doi: 10.1007/s11033-014-3338-8
80. Schroder, C., Matthies, A., Engst, W., Blaut, M., and Braune, A. (2013). Identification and expression of genes involved in the conversion of daidzein and genistein by the equol-forming bacterium Slackia isoflavon-iconvertens. Appl. Environ. Microbiol. 79, 3494-3502. doi: 10.1128/AEM.03693-12
81. Setchell, K. D., and Clerici, C. (2010a). Equol: history, chemistry, and formation.J. Nutr. 140, 1355S-1362S. doi: 10.3945/jn.109.119776
82. Setchell, K. D., and Clerici, C. (2010b). Equol: pharmacokinetics and biological actions. J. Nutr. 140, 1363S-1368S. doi: 10.3945/jn.109.119784
83. Setchell, K. D., Brown, N. M., and Lydeking-Olsen, E. (2002). The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J. Nutr. 132, 3577-3584.
84. Sevrioukova, I. F., Li, H., Zhang, H., Peterson, J. A., and Poulos, T. L. (1999). Structure of a cytochrome P450-redox partner electron-transfer complex. Proc. Natl. Acad. Sci. U.S.A. 96, 1863-1868. doi: 10.1073/pnas.96.5.1863
85. Simkhada, D., Kim, E., Lee, H. C., and Sohng, J. K. (2009). Metabolic engineering of Escherichia coli for the biological synthesis of 7-O-xylosyl naringenin. Mol. Cells 28, 397-401. doi: 10.1007/s10059-009-0135-7
86. Singh, A., Cher Soh, K., Hatzimanikatis, V., and Gill, R. T. (2011). Manipulating redox and ATP balancing for improved production of succinate in E. coli. Metab. Eng. 13, 76-81. doi: 10.1016/j.ymben.2010.10.006
87. Stafford, H. A. (1991). Flavonoid evolution: an enzymic approach. Plant Physiol. 96, 680-685. doi: 10.1104/pp.96.3.680
88. Stapleton, A. E., and Walbot, V. (1994). Flavonoids can protect maize DNA from the induction of ultraviolet radiation damage. Plant Physiol. 105, 881-889. doi: 10.1104/pp.105.3.881
89. Stephanopoulos, G. (2012). Synthetic biology and metabolic engineering. ACS Synth. Biol. 1, 514-525. doi: 10.1021/sb300094q
90. Tai, M., and Stephanopoulos, G. (2013). Engineering the push and pull of lipid biosynthesis in oleaginous yeast Yarrowia lipolytica for biofuel production. Metab. Eng. 15, 1-9. doi: 10.1016/j.ymben.2012.08.007
91. Trantas, E., Panopoulos, N., and Ververidis, F. (2009). Metabolic engineering of the complete pathway leading to heterologous biosynthesis of various flavonoids and stilbenoids in Saccharomyces cerevisiae. Metab. Eng. 11, 355-366. doi: 10.1016/j.ymben.2009.07.004
92. van Summeren-Wesenhagen, P. V., and Marienhagen, J. (2013). Putting bugs to the blush: metabolic engineering for phenylpropanoid-derived products in microorganisms. Bioengineered 4, 355-362. doi: 10.4161/bioe.23885
93. Ververidis, F., Trantas, E., Douglas, C., Vollmer, G., Kretzschmar, G., and Panopoulos, N. (2007). Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: Chemical diversity, impacts on plant biology and human health. Biotechnol. J. 2, 1214-1234. doi: 10.1002/biot.200700084
94. Wang, Z. W., Jiang, C., Wen, Q., Wang, N., Tao, Y. Y., and Xu, L. A. (2014). Deep sequencing of the Camellia chekiangoleosa transcriptome revealed candidate genes for anthocyanin biosynthesis. Gene 538, 1-7. doi: 10.1016/j.gene.2014.01.035
95. Wink, M. (2003). Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry 64, 3-19. doi: 10.1016/S0031-9422(03)00300-5
96. Winkel, B. S. (2004). Metabolic channeling in plants. Annu. Rev. Plant Physiol. Plant Mol. Biol. 55, 85-107. doi: 10.1146/annurev.arplant.55.031903.141714
97. Winkel-Shirley, B. (2001). Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology. Plant Physiol. 126, 485-493. doi: 10.1104/pp.126.2.485
98. Wu, J., Du, G., Zhou, J., and Chen, J. (2013). Metabolic engineering of Escherichia coli for (2S)-pinocembrin production from glucose by a modular metabolic strategy. Metab. Eng. 16, 48-55. doi: 10.1016/j.ymben.2012.11.009
99. Xu, F., Li, L., Zhang, W., Cheng, H., Sun, N., Cheng, S., et al. (2012). Isolation, characterization, and function analysis of a flavonol synthase gene from Ginkgo biloba. Mol. Biol. Rep. 39,2285-2296. doi: 10.1007/s11033-011-0978-9
100. Xu, P., Bhan, N., and Koffas, M. A. (2013a). Engineering plant metabolism into microbes: from systems biology to synthetic biology. Curr. Opin. Biotechnol. 24, 291-299. doi: 10.1016/j.copbio.2012.08.010
101. Xu, P., Gu, Q., Wang, W., Wong, L., Bower, A. G., Collins, C. H., et al. (2013b). Modular optimization of multi-gene pathways for fatty acids production in coli. Nat. Commun. 4, 1409. doi: 10.1038/ncomms2425
102. Xu, P., Li, L., Zhang, F., Stephanopoulos, G., and Koffas, M. (2014a). Improving fatty acids production by engineering dynamic pathway regulation and metabolic control. Proc. Natl. Acad. Sci. U.S.A. 111, 11299-11304. doi: 10.1073/pnas.1406401111
103. Xu, P., Ranganathan, S., Fowler, Z. L., Maranas, C. D., and Koffas, M. A. (2011). Genome-scale metabolic network modeling results in minimal interventions that cooperatively force carbon flux towards malonyl-CoA. Metab. Eng. 13, 578-587. doi: 10.1016/j.ymben.2011.06.008
104. Xu, P., Wang, W., Li, L., Bhan, N., Zhang, F., and Koffas, M. A. (2014b). Design and kinetic analysis of a hybrid promoter-regulator system for malonyl-CoA sensing in Escherichia coli. ACS Chem. Biol. 9, 451-458. doi: 10.1021/cb400623m
105. Yandell, M., and Ence, D. (2012). A beginner’s guide to eukaryotic genome annotation. Nat. Rev. Genet. 13, 329-342. doi: 10.1038/nrg3174
106. Yoon, J.-A., Kim, B.-G., Lee, W. J., Lim, Y., Chong, Y., and Ahn, J.-H. (2012). Production of a novel quercetin glycoside through metabolic engineering of Escherichia coli. Appl. Environ. Microbiol. 78, 4256-4262. doi: 10.1128/AEM.00275-12
107. Zhang, F., Carothers, J. M., and Keasling, J. D. (2012). Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids. Nat. Biotechnol. 30, 354-359. doi: 10.1038/nbt.2149
108. Zhu, S., Wu, J., Du, G., Zhou, J., and Chen, J. (2014). Efficient synthesis of eriodictyol from L-tyrosine in Escherichia coli. Appl. Environ. Microbiol. 80, 3072-3080. doi: 10.1128/AEM.03986-13