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Review Article

利用可再生原料微生物合成药物和营养品的策略

卷 27, 期 28, 2020

页: [4613 - 4621] 页: 9

弟呕挨: 10.2174/0929867327666200212121047

价格: $65

摘要

背景:丰富和可再生的生物材料是各种化学品可持续生产的理想基质，包括天然产品(如药品和营养品)。几十年来，研究人员一直专注于如何设计微生物和开发有效的发酵过程，以从生物材料中过量生产这些分子。尽管取得了许多实验室成果，但要将其中一些转化为成功的工业应用仍是一个挑战。 结果:在此，我们综述了近年来在天然产物生产的代谢工程策略和应用方面的进展。模块化工程方法，如多维启发式过程显着提高效率的优化漫长和复杂的生物合成途径。动态途径调控实现了自主调节，可对代谢碳通量进行重定向，避免有毒中间代谢物的积累。通过引入不同物种之间的竞争或合作，微生物的共同培养促进了天然产物的识别和过度生产。外排工程用于降低产品毒性或克服储存限制，从而提高产品的效价和生产率。 结论:毫无疑问，在自然产物的生物合成方面，许多创新的方法和策略正在逐步催化从实验室到工业的转变。有时，有必要结合两种或两种以上的战略，以获得附加或协同效益。因此，我们可以预见微生物利用可再生生物材料合成药物和营养药品的光明前景。

关键词: 天然产物、次生代谢物、代谢工程、合成生物学、模块化工程、动态调节、微生物共培养、外排工程。

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[1]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod., 2016, 79(3), 629-661.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055] [PMID: 26852623]
[2]
Procópio, R.E.; Silva, I.R.; Martins, M.K.; Azevedo, J.L.; Araújo, J.M. Antibiotics produced by Streptomyces. Braz. J. Infect. Dis., 2012, 16(5), 466-471.
[http://dx.doi.org/10.1016/j.bjid.2012.08.014] [PMID: 22975171]
[3]
Nielsen, J.C.; Grijseels, S.; Prigent, S.; Ji, B.; Dainat, J.; Nielsen, K.F.; Frisvad, J.C.; Workman, M.; Nielsen, J. Global analysis of biosynthetic gene clusters reveals vast potential of secondary metabolite production in Penicillium species. Nat. Microbiol., 2017, 2, 17044.
[http://dx.doi.org/10.1038/nmicrobiol.2017.44] [PMID: 28368369]
[4]
Zhang, C.; Too, HP. Revalorizing lignocellulose for the production of natural pharmaceuticals and other high value bioproducts. Curr. Med. Chem., 2019, 26(14), 2475-2484.
[http://dx.doi.org/10.2174/0929867324666170912095755] [PMID: 28901274]
[5]
Clomburg, J.M.; Crumbley, A.M.; Gonzalez, R. Industrial biomanufacturing: The future of chemical production. Science, 2017, 355(6320) aag0804
[http://dx.doi.org/10.1126/science.aag0804] [PMID: 28059717]
[6]
Belasco, J.G. All things must pass: contrasts and commonalities in eukaryotic and bacterial mRNA decay. Nat. Rev. Mol. Cell Biol., 2010, 11(7), 467-478.
[http://dx.doi.org/10.1038/nrm2917] [PMID: 20520623]
[7]
Rape, M. Ubiquitylation at the crossroads of development and disease. Nat. Rev. Mol. Cell Biol., 2018, 19(1), 59-70.
[http://dx.doi.org/10.1038/nrm.2017.83] [PMID: 28928488]
[8]
Joint Genome Institute (JGI). Genomes Online Database (GOD). Available at: . https://gold.jgi.doe.gov/ (Accessed date: 1st March, 2018)
[9]
Fleischmann, R.D.; Adams, M.D.; White, O.; Clayton, R.A.; Kirkness, E.F.; Kerlavage, A.R.; Bult, C.J.; Tomb, J.F.; Dougherty, B.A.; Merrick, J.M. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science, 1995, 269(5223), 496-512.
[http://dx.doi.org/10.1126/science.7542800] [PMID: 7542800]
[10]
Jain, M.; Koren, S.; Miga, K.H.; Quick, J.; Rand, A.C.; Sasani, T.A.; Tyson, J.R.; Beggs, A.D.; Dilthey, A.T.; Fiddes, I.T.; Malla, S.; Marriott, H.; Nieto, T.; O’Grady, J.; Olsen, H.E.; Pedersen, B.S.; Rhie, A.; Richardson, H.; Quinlan, A.R.; Snutch, T.P.; Tee, L.; Paten, B.; Phillippy, A.M.; Simpson, J.T.; Loman, N.J.; Loose, M. Nanopore sequencing and assembly of a human genome with ultra-long reads. Nat. Biotechnol., 2018, 36(4), 338-345.
[http://dx.doi.org/10.1038/nbt.4060] [PMID: 29431738]
[11]
Ma, S.; Tang, N.; Tian, J.; Synthesis, D.N.A. DNA synthesis, assembly and applications in synthetic biology. Curr. Opin. Chem. Biol., 2012, 16(3-4), 260-267.
[http://dx.doi.org/10.1016/j.cbpa.2012.05.001] [PMID: 22633067]
[12]
Ajikumar, P.K.; Xiao, W-H.; Tyo, K.E.; Wang, Y.; Simeon, F.; Leonard, E.; Mucha, O.; Phon, T.H.; Pfeifer, B.; Stephanopoulos, G. Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science, 2010, 330(6000), 70-74.
[http://dx.doi.org/10.1126/science.1191652] [PMID: 20929806]
[13]
Zhou, K.; Qiao, K.; Edgar, S.; Stephanopoulos, G. Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nat. Biotechnol., 2015, 33(4), 377-383.
[http://dx.doi.org/10.1038/nbt.3095] [PMID: 25558867]
[14]
Thodey, K.; Galanie, S.; Smolke, C.D. A microbial biomanufacturing platform for natural and semisynthetic opioids. Nat. Chem. Biol., 2014, 10(10), 837-844.
[http://dx.doi.org/10.1038/nchembio.1613] [PMID: 25151135]
[15]
Nakagawa, A.; Matsumura, E.; Koyanagi, T.; Katayama, T.; Kawano, N.; Yoshimatsu, K.; Yamamoto, K.; Kumagai, H.; Sato, F.; Minami, H. Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli. Nat. Commun., 2016, 7, 10390.
[http://dx.doi.org/10.1038/ncomms10390] [PMID: 26847395]
[16]
Galanie, S.; Thodey, K.; Trenchard, I.J.; Filsinger Interrante, M.; Smolke, C.D. Complete biosynthesis of opioids in yeast. Science, 2015, 349(6252), 1095-1100.
[http://dx.doi.org/10.1126/science.aac9373] [PMID: 26272907]
[17]
Zhang, C.; Seow, V.Y.; Chen, X.; Too, HP. Multidimensional heuristic process for high-yield production of astaxanthin and fragrance molecules in Escherichia coli. Nat. Commun., 2018, 9(1), 1858.
[http://dx.doi.org/10.1038/s41467-018-04211-x] [PMID: 29752432]
[18]
Zhang, C.; Chen, X.; Zou, R.; Zhou, K.; Stephanopoulos, G.; Too, H-P. Combining genotype improvement and statistical media optimization for isoprenoid production in E. coli. PLoS One, 2013, 8(10) e75164
[http://dx.doi.org/10.1371/journal.pone.0075164] [PMID: 24124471]
[19]
Zhang, C.; Chen, X.; Lindley, N.D.; Too, H.P.A. A “plug-n-play” modular metabolic system for the production of apocarotenoids. Biotechnol. Bioeng., 2018, 115(1), 174-183.
[http://dx.doi.org/10.1002/bit.26462] [PMID: 29077207]
[20]
Paddon, C.J.; Westfall, P.J.; Pitera, D.J.; Benjamin, K.; Fisher, K.; McPhee, D.; Leavell, M.D.; Tai, A.; Main, A.; Eng, D.; Polichuk, D.R.; Teoh, K.H.; Reed, D.W.; Treynor, T.; Lenihan, J.; Fleck, M.; Bajad, S.; Dang, G.; Dengrove, D.; Diola, D.; Dorin, G.; Ellens, K.W.; Fickes, S.; Galazzo, J.; Gaucher, S.P.; Geistlinger, T.; Henry, R.; Hepp, M.; Horning, T.; Iqbal, T.; Jiang, H.; Kizer, L.; Lieu, B.; Melis, D.; Moss, N.; Regentin, R.; Secrest, S.; Tsuruta, H.; Vazquez, R.; Westblade, L.F.; Xu, L.; Yu, M.; Zhang, Y.; Zhao, L.; Lievense, J.; Covello, P.S.; Keasling, J.D.; Reiling, K.K.; Renninger, N.S.; Newman, J.D. High-level semi synthetic production of the potent antimalarial artemisinin. Nature, 2013, 496(7446), 528-532.
[http://dx.doi.org/10.1038/nature12051] [PMID: 23575629]
[21]
Dahl, R.H.; Zhang, F.; Alonso-Gutierrez, J.; Baidoo, E.; Batth, T.S.; Redding-Johanson, A.M.; Petzold, C.J.; Mukhopadhyay, A.; Lee, T.S.; Adams, P.D.; Keasling, J.D. Engineering dynamic pathway regulation using stress-response promoters. Nat. Biotechnol., 2013, 31(11), 1039-1046.
[http://dx.doi.org/10.1038/nbt.2689] [PMID: 24142050]
[22]
Zhang, C.; Zou, R.; Chen, X.; Stephanopoulos, G.; Too, HP. Experimental design-aided systematic pathway optimization of glucose uptake and deoxyxylulose phosphate pathway for improved amorphadiene production. Appl. Microbiol. Biotechnol., 2015, 99(9), 3825-3837.
[http://dx.doi.org/10.1007/s00253-015-6463-y] [PMID: 25715782]
[23]
Zhang, C.; Chen, X.; Stephanopoulos, G.; Too, HP. Efflux transporter engineering markedly improves amorphadiene production in Escherichia coli. Biotechnol. Bioeng., 2016, 113(8), 1755-1763.
[http://dx.doi.org/10.1002/bit.25943] [PMID: 26804325]
[24]
Chen, X.; Zhang, C.; Zou, R.; Stephanopoulos, G.; Too, HP. In vitro metabolic engineering of amorpha-4,11-diene biosynthesis at enhanced rate and specific yield of production. ACS Synth. Biol., 2017, 6(9), 1691-1700.
[http://dx.doi.org/10.1021/acssynbio.6b00377] [PMID: 28520394]
[25]
Jin, E.; Wong, L.; Jiao, Y.; Engel, J.; Holdridge, B.; Xu, P. Rapid evolution of regulatory element libraries for tunable transcriptional and translational control of gene expression. Synth Syst Biotechnol, 2017, 2(4), 295-301.
[http://dx.doi.org/10.1016/j.synbio.2017.10.003] [PMID: 29552654]
[26]
Vasilakou, E.; Machado, D.; Theorell, A.; Rocha, I.; Nöh, K.; Oldiges, M.; Wahl, S.A. Current state and challenges for dynamic metabolic modeling. Curr. Opin. Microbiol., 2016, 33, 97-104.
[http://dx.doi.org/10.1016/j.mib.2016.07.008] [PMID: 27472025]
[27]
Smanski, M.J.; Bhatia, S.; Zhao, D.; Park, Y.; B A Woodruff, L.; Giannoukos, G.; Ciulla, D.; Busby, M.; Calderon, J.; Nicol, R.; Gordon, D.B.; Densmore, D.; Voigt, C.A. Functional optimization of gene clusters by combinatorial design and assembly. Nat. Biotechnol., 2014, 32(12), 1241-1249.
[http://dx.doi.org/10.1038/nbt.3063] [PMID: 25419741]
[28]
Farmer, W.R.; Liao, J.C. Improving lycopene production in Escherichia coli by engineering metabolic control. Nat. Biotechnol., 2000, 18(5), 533-537.
[http://dx.doi.org/10.1038/75398] [PMID: 10802621]
[29]
Martin, V.J.; Pitera, D.J.; Withers, S.T.; Newman, J.D.; Keasling, J.D. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat. Biotechnol., 2003, 21(7), 796-802.
[http://dx.doi.org/10.1038/nbt833] [PMID: 12778056]
[30]
Xu, P.; Li, L.; Zhang, F.; Stephanopoulos, G.; Koffas, M. Improving fatty acids production by engineering dynamic pathway regulation and metabolic control. Proc. Natl. Acad. Sci. USA, 2014, 111(31), 11299-11304.
[http://dx.doi.org/10.1073/pnas.1406401111] [PMID: 25049420]
[31]
Xu, P.; Bhan, N.; Koffas, M.A.G. Engineering plant metabolism into microbes: from systems biology to synthetic biology. Curr. Opin. Biotechnol., 2013, 24(2), 291-299.
[http://dx.doi.org/10.1016/j.copbio.2012.08.010] [PMID: 22985679]
[32]
Gupta, A.; Reizman, I.M.; Reisch, C.R.; Prather, K.L. Dynamic regulation of metabolic flux in engineered bacteria using a pathway-independent quorum-sensing circuit. Nat. Biotechnol., 2017, 35(3), 273-279.
[http://dx.doi.org/10.1038/nbt.3796] [PMID: 28191902]
[33]
Xu, P. Production of chemicals using dynamic control of metabolic fluxes. Curr. Opin. Biotechnol., 2018, 53, 12-19.
[http://dx.doi.org/10.1016/j.copbio.2017.10.009] [PMID: 29145021]
[34]
Xu, P.; Rizzoni, E.A.; Sul, S.Y.; Stephanopoulos, G. Improving metabolic pathway efficiency by statistical model-based multivariate regulatory metabolic engineering. ACS Synth. Biol., 2017, 6(1), 148-158.
[http://dx.doi.org/10.1021/acssynbio.6b00187] [PMID: 27490704]
[35]
Faust, K.; Raes, J. Microbial interactions: from networks to models. Nat. Rev. Microbiol., 2012, 10(8), 538-550.
[http://dx.doi.org/10.1038/nrmicro2832] [PMID: 22796884]
[36]
Netzker, T.; Fischer, J.; Weber, J.; Mattern, D.J.; König, C.C.; Valiante, V.; Schroeckh, V.; Brakhage, A.A. Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters. Front. Microbiol., 2015, 6, 299.
[http://dx.doi.org/10.3389/fmicb.2015.00299] [PMID: 25941517]
[37]
Nützmann, H.W.; Reyes-Dominguez, Y.; Scherlach, K.; Schroeckh, V.; Horn, F.; Gacek, A.; Schümann, J.; Hertweck, C.; Strauss, J.; Brakhage, A.A. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. Proc. Natl. Acad. Sci. USA, 2011, 108(34), 14282-14287.
[http://dx.doi.org/10.1073/pnas.1103523108] [PMID: 21825172]
[38]
Park, H.B.; Kwon, H.C.; Lee, C.H.; Yang, H.O. Glionitrin A, an antibiotic-antitumor metabolite derived from competitive interaction between abandoned mine microbes. J. Nat. Prod., 2009, 72(2), 248-252.
[http://dx.doi.org/10.1021/np800606e] [PMID: 19159274]
[39]
Ola, A.R.; Thomy, D.; Lai, D.; Brötz-Oesterhelt, H.; Proksch, P. Inducing secondary metabolite production by the endophytic fungus Fusarium tricinctum through coculture with Bacillus subtilis. J. Nat. Prod., 2013, 76(11), 2094-2099.
[http://dx.doi.org/10.1021/np400589h] [PMID: 24175613]
[40]
Zhang, H.; Pereira, B.; Li, Z.; Stephanopoulos, G. Engineering Escherichia coli coculture systems for the production of biochemical products. Proc. Natl. Acad. Sci. USA, 2015, 112(27), 8266-8271.
[http://dx.doi.org/10.1073/pnas.1506781112] [PMID: 26111796]
[41]
Minty, J.J.; Singer, M.E.; Scholz, S.A.; Bae, C.H.; Ahn, J.H.; Foster, C.E.; Liao, J.C.; Lin, X.N. Design and characterization of synthetic fungal-bacterial consortia for direct production of isobutanol from cellulosic biomass. Proc. Natl. Acad. Sci. USA, 2013, 110(36), 14592-14597.
[http://dx.doi.org/10.1073/pnas.1218447110] [PMID: 23959872]
[42]
Jones, J.A.; Vernacchio, V.R.; Collins, S.M.; Shirke, A.N.; Xiu, Y.; Englaender, J.A.; Cress, B.F.; McCutcheon, C.C.; Linhardt, R.J.; Gross, R.A.; Koffas, M.A.G. complete biosynthesis of anthocyanins using E. coli polycultures. MBio, 2017, 8(3), e00621-e17.
[http://dx.doi.org/10.1128/mBio.00621-17] [PMID: 28588129]
[43]
Brohée, S.; Barriot, R.; Moreau, Y.; André, B. YTPdb: a wiki database of yeast membrane transporters. Biochim. Biophys. Acta, 2010, 1798(10), 1908-1912.
[http://dx.doi.org/10.1016/j.bbamem.2010.06.008] [PMID: 20599686]
[44]
Daley, D.O.; Rapp, M.; Granseth, E.; Melén, K.; Drew, D.; von Heijne, G. Global topology analysis of the Escherichia coli inner membrane proteome. Science, 2005, 308(5726), 1321-1323.
[http://dx.doi.org/10.1126/science.1109730] [PMID: 15919996]
[45]
Piddock, L.J. Multidrug-resistance efflux pumps - not just for resistance. Nat. Rev. Microbiol., 2006, 4(8), 629-636.
[http://dx.doi.org/10.1038/nrmicro1464] [PMID: 16845433]
[46]
Dunlop, M.J.; Dossani, Z.Y.; Szmidt, H.L.; Chu, H.C.; Lee, T.S.; Keasling, J.D.; Hadi, M.Z.; Mukhopadhyay, A. Engineering microbial biofuel tolerance and export using efflux pumps. Mol. Syst. Biol., 2011, 7, 487.
[http://dx.doi.org/10.1038/msb.2011.21] [PMID: 21556065]
[47]
Foo, J.L.; Leong, S.S.J. Directed evolution of an E. coli inner membrane transporter for improved efflux of biofuel molecules. Biotechnol. Biofuels, 2013, 6(1), 81.
[http://dx.doi.org/10.1186/1754-6834-6-81] [PMID: 23693002]
[48]
Wang, J-F.; Xiong, Z-Q.; Li, S-Y.; Wang, Y. Enhancing isoprenoid production through systematically assembling and modulating efflux pumps in Escherichia coli. Appl. Microbiol. Biotechnol., 2013, 97(18), 8057-8067.
[http://dx.doi.org/10.1007/s00253-013-5062-z] [PMID: 23864262]
[49]
Foo, J.L.; Jensen, H.M.; Dahl, R.H.; George, K.; Keasling, J.D.; Lee, T.S.; Leong, S.; Mukhopadhyay, A. Improving microbial biogasoline production in Escherichia coli using tolerance engineering. MBio, 2014, 5(6), e01932-e01914.
[http://dx.doi.org/10.1128/mBio.01932-14] [PMID: 25370492]
[50]
Verhoef, S.; Ballerstedt, H.; Volkers, R.J.M.; de Winde, J.H.; Ruijssenaars, H.J. Comparative transcriptomics and proteomics of p-hydroxybenzoate producing Pseudomonas putida S12: novel responses and implications for strain improvement. Appl. Microbiol. Biotechnol., 2010, 87(2), 679-690.
[http://dx.doi.org/10.1007/s00253-010-2626-z] [PMID: 20449741]
[51]
Ling, H.; Chen, B.; Kang, A.; Lee, J.M.; Chang, M.W. Transcriptome response to alkane biofuels in Saccharomyces cerevisiae: identification of efflux pumps involved in alkane tolerance. Biotechnol. Biofuels, 2013, 6(1), 95.
[http://dx.doi.org/10.1186/1754-6834-6-95] [PMID: 23826995]
[52]
Doshi, R.; Nguyen, T.; Chang, G. Transporter-mediated biofuel secretion. Proc. Natl. Acad. Sci. USA, 2013, 110(19), 7642-7647.
[http://dx.doi.org/10.1073/pnas.1301358110] [PMID: 23613592]
[53]
Alvizo, O.; Nguyen, L.J.; Savile, C.K.; Bresson, J.A.; Lakhapatri, S.L.; Solis, E.O.; Fox, R.J.; Broering, J.M.; Benoit, M.R.; Zimmerman, S.A.; Novick, S.J.; Liang, J.; Lalonde, J.J. Directed evolution of an ultrastable carbonic anhydrase for highly efficient carbon capture from flue gas. Proc. Natl. Acad. Sci. USA, 2014, 111(46), 16436-16441.
[http://dx.doi.org/10.1073/pnas.1411461111] [PMID: 25368146]
[54]
Gupta, R.D.; Goldsmith, M.; Ashani, Y.; Simo, Y.; Mullokandov, G.; Bar, H.; Ben-David, M.; Leader, H.; Margalit, R.; Silman, I.; Sussman, J.L.; Tawfik, D.S. Directed evolution of hydrolases for prevention of G-type nerve agent intoxication. Nat. Chem. Biol., 2011, 7(2), 120-125.
[http://dx.doi.org/10.1038/nchembio.510] [PMID: 21217689]
[55]
Leonard, E.; Ajikumar, P.K.; Thayer, K.; Xiao, W-H.; Mo, J.D.; Tidor, B.; Stephanopoulos, G.; Prather, K.L. Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control. Proc. Natl. Acad. Sci. USA, 2010, 107(31), 13654-13659.
[http://dx.doi.org/10.1073/pnas.1006138107] [PMID: 20643967]
[56]
Schwander, T.; Schada von Borzyskowski, L.; Burgener, S.; Cortina, N.S.; Erb, T.J. A synthetic pathway for the fixation of carbon dioxide in vitro. Science, 2016, 354(6314), 900-904.
[http://dx.doi.org/10.1126/science.aah5237] [PMID: 27856910]
[57]
Meadows, A.L.; Hawkins, K.M.; Tsegaye, Y.; Antipov, E.; Kim, Y.; Raetz, L.; Dahl, R.H.; Tai, A.; Mahatdejkul-Meadows, T.; Xu, L.; Zhao, L.; Dasika, M.S.; Murarka, A.; Lenihan, J.; Eng, D.; Leng, J.S.; Liu, C.L.; Wenger, J.W.; Jiang, H.; Chao, L.; Westfall, P.; Lai, J.; Ganesan, S.; Jackson, P.; Mans, R.; Platt, D.; Reeves, C.D.; Saija, P.R.; Wichmann, G.; Holmes, V.F.; Benjamin, K.; Hill, P.W.; Gardner, T.S.; Tsong, A.E. Rewriting yeast central carbon metabolism for industrial isoprenoid production. Nature, 2016, 537(7622), 694-697.
[http://dx.doi.org/10.1038/nature19769] [PMID: 27654918]
[58]
Shaw, A.J.; Lam, F.H.; Hamilton, M.; Consiglio, A.; MacEwen, K.; Brevnova, E.E.; Greenhagen, E.; LaTouf, W.G.; South, C.R.; van Dijken, H.; Stephanopoulos, G. Metabolic engineering of microbial competitive advantage for industrial fermentation processes. Science, 2016, 353(6299), 583-586.
[http://dx.doi.org/10.1126/science.aaf6159] [PMID: 27493184]

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