大肠杆菌微细胞工厂生产萜类化合物研究进展
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摘要
萜类化合物(terpenoids)是自然界中分布最广泛的天然产物,因其多样的生理活性和经济价值而被人们认识和开发。近年来,代谢工程及合成生物学的发展使得生物合成萜类化合物备受关注。本文中,笔者总结了萜类化合物合成的路线及其在大肠杆菌研究中取得的进展,探讨和展望了可能的发展方向,为大肠杆菌微细胞工厂合成萜类产物的研究提供参考和启示。
Terpenoids are recognized and mined owing to their physiological and economical properties.With the developments of metabolic engineering and synthetic biology,biosynthesis of these most diverse products in nature receives much more attentions. Our review summarizes their biosynthetic routes and recent progresses using Escherichia coli as a host,and discusses the perspectives. It is anticipated to emphasize understanding of microbial cell factory development for terpenoids synthesis in E. coli.
Terpenoids are recognized and mined owing to their physiological and economical properties.With the developments of metabolic engineering and synthetic biology,biosynthesis of these most diverse products in nature receives much more attentions. Our review summarizes their biosynthetic routes and recent progresses using Escherichia coli as a host,and discusses the perspectives. It is anticipated to emphasize understanding of microbial cell factory development for terpenoids synthesis in E. coli.
引文
[1] GEORGE K W,ALONSO-GUTIERREZ J,KEASLING J D,et al.Isoprenoid drugs,biofuels,and chemicals:artemisinin,farnesene,and beyond[J]. Adv Biochem Eng Biotechnol,2015,148:355-389.
[2] ZYAD A,TILAOUI M,JAAFARI A,et al.More insights into the pharmacological effects of artemisinin[J]. Phytother Res,2018,32(2):216-229.
[3] AJIKUMAR P K,XIAO W H,TYO K E,et al.Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli[J].Science,2010,330:70-74.
[4] LIU T,KHOSLA C.A balancing act for taxol precursor pathways in E. coli[J].Science,2010,330:44-45.
[5]孙丽超,李淑英,王凤忠,等.萜类化合物的合成生物学研究进展[J].生物技术通报,2017,33(1):64-75.
[6]王倩,康振,梁泉峰,等.合成未来:从大肠杆菌的重构看合成生物学的发展[J].生命科学,2011,23(9):844-848.
[7]杨祖明,李炳志.代谢工程技术方法研究进展[J].生物加工过程,2018,16(1):1-11.
[8]邵洁,李建华,王凯博,等.植物底盘:天然产物合成生物学研究的新热点[J].生物加工过程,2017,15(5):24-31.
[9]张中素,杨瑞刚,朱凌云,等.提高微生物合成萜类化合物产量的策略[J].中国生物工程杂志,2017,37(1):97-103.
[10] BIAN G,DENG Z,LIU T.Strategies for terpenoid overproduction and new terpenoid discovery[J].Curr Opin Biotechnol,2017,48:234-241.
[11] FRANK A,GROLL M.The methylerythritol phosphate pathway to isoprenoids[J].Chem Rev,2017,117(8):5675-5703.
[12] LIAO P,HEMMERLIN A,BACH T J,et al.The potential of the mevalonate pathway for enhanced isoprenoid production[J].Biotechnol Adv,2016,34(5):697-713.
[13] DELLAS N,THOMAS S T,MANNING G,et al. Discovery of a metabolic alternative to the classical mevalonate pathway[J].Elife,2013,2:e00672.
[14] GROCHOWSKI L L,XU H,WHITE R H. Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate[J]. J Bacteriol,2006,188(9):3192-3198.
[15]李军玲,罗晓东,赵沛基,等.植物萜类生物合成中的后修饰酶[J].云南植物研究,2009,31(5):461-468.
[16] BANERJEE A,SHARKEY T D. Methylerythritol 4-phosphate(MEP)pathway metabolic regulation[J]. Nat Prod Rep,2014,31:1043-1055.
[17] LV X,XU H,YU H.Significantly enhanced production of isoprene by ordered coexpression of genes dxs,dxr,and idi in Escherichia coli[J].Appl Microbiol Biotechnol,2013,97:2357-2365.
[18] ZHAO J,LI Q,SUN T. et al. Engineering central metabolic modules of Escherichia coli for improvingβ-carotene production[J].Metab Eng,2013,17:42-50.
[19] FARMER W R,LIAO J C. Precursor balancing for metabolic engineering of lycopene production in Escherichia coli[J].Biotechnol Prog,2001,17(1):57-61.
[20] LIU H,SUN Y,RAMOS K R,et al. Combination of EntnerDoudoroff pathway with MEP increases isoprene production in engineered Escherichia coli[J].PLoS ONE,2013,8:e83290.
[21] LIU H,WANG Y,TANG Q,et al. MEP pathway-mediated isopentenol production in metabolically engineered Escherichia coli[J].Microb Cell Fact,2014,13:135.
[22] ZHOU J,YANG L,WANG C,et al.Enhanced performance of the methylerythritol phosphate pathway by manipulation of redox reactions relevant to IspC,IspG,and IspH[J]. J Biotechnol,2017,248:1-8.
[23] ZHOU K,ZOU R,STEPHANOPOULOS G,et al. Metabolite profiling identified methylerythritol cyclodiphosphate efflux as a limiting step in microbial isoprenoid production[J]. PLoS ONE,2012,7:e47513.
[24] ZOU R,ZHOU K,STEPHANOPOULOS G,et al. Combinatorial engineering of 1-deoxy-D-xylulose 5-phosphate pathway using cross-lapping in vitro assembly(CLIVA)method[J]. PLoS ONE,2013,8:e79557.
[25] LI Q,FAN F,GAO X,et al.Balanced activation of Isp G and Isp H to eliminate MEP intermediate accumulation and improve isoprenoids production in Escherichia coli[J]. Metab Eng,2017,44:13-21.
[26] KING J R,WOOLSTON B M,STEPHANOPOULOS G.Designing a new entry point into isoprenoid metabolism by exploiting fructose-6-phosphate aldolase side reactivity of Escherichia coli[J].ACS Synth Biol,2017,6(7):1416-1426.
[27] MARTIN V J,PITERA D J,WITHERS S T,et al.Engineering a mevalonate pathway in Escherichia coli for production of terpenoids[J].Nat Biotechnol,2003,21:796-802.
[28] PERALTA-YAHYA P P,OUELLET M,CHAN R,et al.Identification and microbial production of a terpene-based advanced biofuel[J].Nat Commun,2011,2:483.
[29] YANG L,WANG C,ZHOU J,et al.Combinatorial engineering of hybrid mevalonate pathways in Escherichia coli for protoilludene production[J].Microb Cell Fact,2016,15:14.
[30] ZHU F,ZHONG X,HU M,et al. In vitro reconstitution of mevalonate pathway and targeted engineering of farnesene overproduction in Escherichia coli[J]. Biotechnol Bioeng,2014,111(7):1396-1405.
[31] CHOU H H,KEASLING J D. Programming adaptive control to evolve increased metabolite production[J]. Nat Commun,2013,4:2595.
[32] DAHL R H,ZHANG F,ALONSO-GUTIERREZ J,et al.Engineering dynamic pathway regulation using stress-response promoters[J].Nat Biotechnol,2013,31(11):1039-1046.
[33] SHEN H J,CHENG B Y,ZHANG Y M,et al.Dynamic control of the mevalonate pathway expression for improved zeaxanthin production in Escherichia coli and comparative proteome analysis[J].Metab Eng,2016,38:180-190.
[34] KIM E M,WOO H M,TIAN T,et al. Autonomous control of metabolic state by a quorum sensing(QS)-mediated regulator for bisabolene production in engineered E.coli[J].Metab Eng,2017,44:325-336.
[35] HAN G H,KIM S K,YOON P K,et al.Fermentative production and direct extraction of(-)-α-bisabolol in metabolically engineered Escherichia coli[J].Microb Cell Fact,2016,15:185.
[36] WHITED G M,FEHER F J,BENKO D A,et al.Development of a gas-phase bioprocess for isoprenemonomer production using metabolic pathway engineering[J]. Ind Biotechnol,2010,6(3):152-163.
[37] KANG A,GEORGE K W,WANG G,et al. Isopentenyl diphosphate(IPP)-bypass mevalonate pathways for isopentenol production[J].Metab Eng,2016,34:25-35.
[38] YANG C, GAO X,JIANG Y, et al. Synergy between methylerythritol phosphate pathway and mevalonate pathway for isoprene production in Escherichia coli[J].Metab Eng,2016,37:79-91.
[39] LEONARD E,AJIKUMAR P K,THAYER K,et al. Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control[J]. Proc Natl Acad Sci USA,2010,107:13654-13659.
[40] YOSHIKUNI Y,FERRIN T E,KEASLING J D. Designed divergent evolution of enzyme function[J]. Nature,2006,440:1078-1082.
[41] BIAN G,HAN Y,HOU A,et al.Releasing the potential power of terpene synthases by a robust precursor supply platform[J].Metab Eng,2017,42:1-8.
[42] WANG C,PARK J E,CHOI E S,et al. Farnesol production in Escherichia coli through the construction of a farnesol biosynthesis pathway:application of PgpB and Ybj G phosphatases[J].Biotechnol J,2016.11:1291-1297
[43] CHOU H H,KEASLING J D.Synthetic pathway for production of five-carbon alcohols from isopentenyl diphosphate[J]. Appl Environ Microbiol,2012,78:7849-7855.
[44] WITHERS S T,GOTTLIEB S S,LIEU B,et al. Identification of isopentenol biosynthetic genes from Bacillus subtilis by a screening method based on isoprenoid precursor toxicity[J].Appl Environ Microbiol,2007,73(19):6277-6283.
[45] GEORGE K W,THOMPSON M G,KANG A,et al. Metabolic engineering for the high-yield production of isoprenoid-based C5alcohols in E.coli[J].Sci Rep,2015,5:11128.
[46] CHANG M C,EACHUS R A,TRIEU W,et al. Engineering Escherichia coli for production of functionalized terpenoids using plant P450s[J].Nat Chem Biol,2007,3(5):274-277.
[47] BIGGS B W,LIM C G,SAGLIANI K,et al. Overcoming heterologous protein interdependency to optimize P450-mediated taxol precursor synthesis in Escherichia coli[J]. Proc Natl Acad Sci USA,2016,113:3209-3214.
[48] JOHNS N I,BLAZEJEWSKI T,GOMES A L,et al.Principles for designing synthetic microbial communities[J]. Curr Opin Microbiol,2016,31:146-153.
[49] GOH W W B,WONG L. Integrating networks and proteomics:moving forward[J].Trends Biotechnol,2016,34:951-959.
[50] CAMPBELL K,XIA J,NIELSEN J.The impact of systems biology on bioprocessing[J].Trends Biotechnol,2017,35:1156-1168.
[51]陈修来,高聪,刘佳,等.微生物代谢路径的优化与调控[J].生物加工过程,2017,15(5):1-8.
[52] WANG C,YOON S H,SHAH A A,et al.Farnesol production from Escherichia coli by harnessing the exogenous mevalonate pathway[J].Biotechnol Bioeng,2010,107:421-429.
[53] DUNLOP M J,DOSSANI Z Y,SZMIDT H L,et al. Engineering microbial biofuel tolerance and export using efflux pumps[J].Mol Syst Biol,2011,7:487.
[54] TURNER W J,DUNLOP M J. Trade-offs in improving biofuel tolerance using combinations of efflux pumps[J]. ACS Synth Biol,2015,4(10):1056-1063.
[55] DOSHI R,NGUYEN T,CHANG G.Transporter-mediated biofuel secretion[J].Proc Natl Acad Sci USA,2013,110:7642-7647.
[56] WU T,YE L,ZHAO D,et al. Membrane engineering:a novel strategy to enhance the production and accumulation ofβ-carotene in Escherichia coli[J].Metab Eng,2017,43:85-91.
[2] ZYAD A,TILAOUI M,JAAFARI A,et al.More insights into the pharmacological effects of artemisinin[J]. Phytother Res,2018,32(2):216-229.
[3] AJIKUMAR P K,XIAO W H,TYO K E,et al.Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli[J].Science,2010,330:70-74.
[4] LIU T,KHOSLA C.A balancing act for taxol precursor pathways in E. coli[J].Science,2010,330:44-45.
[5]孙丽超,李淑英,王凤忠,等.萜类化合物的合成生物学研究进展[J].生物技术通报,2017,33(1):64-75.
[6]王倩,康振,梁泉峰,等.合成未来:从大肠杆菌的重构看合成生物学的发展[J].生命科学,2011,23(9):844-848.
[7]杨祖明,李炳志.代谢工程技术方法研究进展[J].生物加工过程,2018,16(1):1-11.
[8]邵洁,李建华,王凯博,等.植物底盘:天然产物合成生物学研究的新热点[J].生物加工过程,2017,15(5):24-31.
[9]张中素,杨瑞刚,朱凌云,等.提高微生物合成萜类化合物产量的策略[J].中国生物工程杂志,2017,37(1):97-103.
[10] BIAN G,DENG Z,LIU T.Strategies for terpenoid overproduction and new terpenoid discovery[J].Curr Opin Biotechnol,2017,48:234-241.
[11] FRANK A,GROLL M.The methylerythritol phosphate pathway to isoprenoids[J].Chem Rev,2017,117(8):5675-5703.
[12] LIAO P,HEMMERLIN A,BACH T J,et al.The potential of the mevalonate pathway for enhanced isoprenoid production[J].Biotechnol Adv,2016,34(5):697-713.
[13] DELLAS N,THOMAS S T,MANNING G,et al. Discovery of a metabolic alternative to the classical mevalonate pathway[J].Elife,2013,2:e00672.
[14] GROCHOWSKI L L,XU H,WHITE R H. Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate[J]. J Bacteriol,2006,188(9):3192-3198.
[15]李军玲,罗晓东,赵沛基,等.植物萜类生物合成中的后修饰酶[J].云南植物研究,2009,31(5):461-468.
[16] BANERJEE A,SHARKEY T D. Methylerythritol 4-phosphate(MEP)pathway metabolic regulation[J]. Nat Prod Rep,2014,31:1043-1055.
[17] LV X,XU H,YU H.Significantly enhanced production of isoprene by ordered coexpression of genes dxs,dxr,and idi in Escherichia coli[J].Appl Microbiol Biotechnol,2013,97:2357-2365.
[18] ZHAO J,LI Q,SUN T. et al. Engineering central metabolic modules of Escherichia coli for improvingβ-carotene production[J].Metab Eng,2013,17:42-50.
[19] FARMER W R,LIAO J C. Precursor balancing for metabolic engineering of lycopene production in Escherichia coli[J].Biotechnol Prog,2001,17(1):57-61.
[20] LIU H,SUN Y,RAMOS K R,et al. Combination of EntnerDoudoroff pathway with MEP increases isoprene production in engineered Escherichia coli[J].PLoS ONE,2013,8:e83290.
[21] LIU H,WANG Y,TANG Q,et al. MEP pathway-mediated isopentenol production in metabolically engineered Escherichia coli[J].Microb Cell Fact,2014,13:135.
[22] ZHOU J,YANG L,WANG C,et al.Enhanced performance of the methylerythritol phosphate pathway by manipulation of redox reactions relevant to IspC,IspG,and IspH[J]. J Biotechnol,2017,248:1-8.
[23] ZHOU K,ZOU R,STEPHANOPOULOS G,et al. Metabolite profiling identified methylerythritol cyclodiphosphate efflux as a limiting step in microbial isoprenoid production[J]. PLoS ONE,2012,7:e47513.
[24] ZOU R,ZHOU K,STEPHANOPOULOS G,et al. Combinatorial engineering of 1-deoxy-D-xylulose 5-phosphate pathway using cross-lapping in vitro assembly(CLIVA)method[J]. PLoS ONE,2013,8:e79557.
[25] LI Q,FAN F,GAO X,et al.Balanced activation of Isp G and Isp H to eliminate MEP intermediate accumulation and improve isoprenoids production in Escherichia coli[J]. Metab Eng,2017,44:13-21.
[26] KING J R,WOOLSTON B M,STEPHANOPOULOS G.Designing a new entry point into isoprenoid metabolism by exploiting fructose-6-phosphate aldolase side reactivity of Escherichia coli[J].ACS Synth Biol,2017,6(7):1416-1426.
[27] MARTIN V J,PITERA D J,WITHERS S T,et al.Engineering a mevalonate pathway in Escherichia coli for production of terpenoids[J].Nat Biotechnol,2003,21:796-802.
[28] PERALTA-YAHYA P P,OUELLET M,CHAN R,et al.Identification and microbial production of a terpene-based advanced biofuel[J].Nat Commun,2011,2:483.
[29] YANG L,WANG C,ZHOU J,et al.Combinatorial engineering of hybrid mevalonate pathways in Escherichia coli for protoilludene production[J].Microb Cell Fact,2016,15:14.
[30] ZHU F,ZHONG X,HU M,et al. In vitro reconstitution of mevalonate pathway and targeted engineering of farnesene overproduction in Escherichia coli[J]. Biotechnol Bioeng,2014,111(7):1396-1405.
[31] CHOU H H,KEASLING J D. Programming adaptive control to evolve increased metabolite production[J]. Nat Commun,2013,4:2595.
[32] DAHL R H,ZHANG F,ALONSO-GUTIERREZ J,et al.Engineering dynamic pathway regulation using stress-response promoters[J].Nat Biotechnol,2013,31(11):1039-1046.
[33] SHEN H J,CHENG B Y,ZHANG Y M,et al.Dynamic control of the mevalonate pathway expression for improved zeaxanthin production in Escherichia coli and comparative proteome analysis[J].Metab Eng,2016,38:180-190.
[34] KIM E M,WOO H M,TIAN T,et al. Autonomous control of metabolic state by a quorum sensing(QS)-mediated regulator for bisabolene production in engineered E.coli[J].Metab Eng,2017,44:325-336.
[35] HAN G H,KIM S K,YOON P K,et al.Fermentative production and direct extraction of(-)-α-bisabolol in metabolically engineered Escherichia coli[J].Microb Cell Fact,2016,15:185.
[36] WHITED G M,FEHER F J,BENKO D A,et al.Development of a gas-phase bioprocess for isoprenemonomer production using metabolic pathway engineering[J]. Ind Biotechnol,2010,6(3):152-163.
[37] KANG A,GEORGE K W,WANG G,et al. Isopentenyl diphosphate(IPP)-bypass mevalonate pathways for isopentenol production[J].Metab Eng,2016,34:25-35.
[38] YANG C, GAO X,JIANG Y, et al. Synergy between methylerythritol phosphate pathway and mevalonate pathway for isoprene production in Escherichia coli[J].Metab Eng,2016,37:79-91.
[39] LEONARD E,AJIKUMAR P K,THAYER K,et al. Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control[J]. Proc Natl Acad Sci USA,2010,107:13654-13659.
[40] YOSHIKUNI Y,FERRIN T E,KEASLING J D. Designed divergent evolution of enzyme function[J]. Nature,2006,440:1078-1082.
[41] BIAN G,HAN Y,HOU A,et al.Releasing the potential power of terpene synthases by a robust precursor supply platform[J].Metab Eng,2017,42:1-8.
[42] WANG C,PARK J E,CHOI E S,et al. Farnesol production in Escherichia coli through the construction of a farnesol biosynthesis pathway:application of PgpB and Ybj G phosphatases[J].Biotechnol J,2016.11:1291-1297
[43] CHOU H H,KEASLING J D.Synthetic pathway for production of five-carbon alcohols from isopentenyl diphosphate[J]. Appl Environ Microbiol,2012,78:7849-7855.
[44] WITHERS S T,GOTTLIEB S S,LIEU B,et al. Identification of isopentenol biosynthetic genes from Bacillus subtilis by a screening method based on isoprenoid precursor toxicity[J].Appl Environ Microbiol,2007,73(19):6277-6283.
[45] GEORGE K W,THOMPSON M G,KANG A,et al. Metabolic engineering for the high-yield production of isoprenoid-based C5alcohols in E.coli[J].Sci Rep,2015,5:11128.
[46] CHANG M C,EACHUS R A,TRIEU W,et al. Engineering Escherichia coli for production of functionalized terpenoids using plant P450s[J].Nat Chem Biol,2007,3(5):274-277.
[47] BIGGS B W,LIM C G,SAGLIANI K,et al. Overcoming heterologous protein interdependency to optimize P450-mediated taxol precursor synthesis in Escherichia coli[J]. Proc Natl Acad Sci USA,2016,113:3209-3214.
[48] JOHNS N I,BLAZEJEWSKI T,GOMES A L,et al.Principles for designing synthetic microbial communities[J]. Curr Opin Microbiol,2016,31:146-153.
[49] GOH W W B,WONG L. Integrating networks and proteomics:moving forward[J].Trends Biotechnol,2016,34:951-959.
[50] CAMPBELL K,XIA J,NIELSEN J.The impact of systems biology on bioprocessing[J].Trends Biotechnol,2017,35:1156-1168.
[51]陈修来,高聪,刘佳,等.微生物代谢路径的优化与调控[J].生物加工过程,2017,15(5):1-8.
[52] WANG C,YOON S H,SHAH A A,et al.Farnesol production from Escherichia coli by harnessing the exogenous mevalonate pathway[J].Biotechnol Bioeng,2010,107:421-429.
[53] DUNLOP M J,DOSSANI Z Y,SZMIDT H L,et al. Engineering microbial biofuel tolerance and export using efflux pumps[J].Mol Syst Biol,2011,7:487.
[54] TURNER W J,DUNLOP M J. Trade-offs in improving biofuel tolerance using combinations of efflux pumps[J]. ACS Synth Biol,2015,4(10):1056-1063.
[55] DOSHI R,NGUYEN T,CHANG G.Transporter-mediated biofuel secretion[J].Proc Natl Acad Sci USA,2013,110:7642-7647.
[56] WU T,YE L,ZHAO D,et al. Membrane engineering:a novel strategy to enhance the production and accumulation ofβ-carotene in Escherichia coli[J].Metab Eng,2017,43:85-91.