微生物辅因子平衡的代谢调控
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摘要
辅因子平衡对于酶制剂、药品和化学品的生产具有重要的作用。为了满足工业化生产的需求,维持辅因子长期有效的平衡是实现代谢流高效化导向目标代谢产物的必要手段。本文在总结辅因子生理功能的基础上,从生化工程和代谢工程两方面分析归纳了辅因子的代谢调控策略,并展望了辅因子进一步精深调控的发展方向。
Cofactor balance plays an important role in producing enzymes, pharmaceuticals and chemicals. To meet the demand of industrial production, microbes should maintain a maximal carbon flux towards target metabolites without fluctuations in cofactor. We reviewed the physiological function of cofactor and discussed detailed strategies to manipulate cofactor balance through biochemical engineering and metabolic engineering. Furthermore, we indicated future research needs to further regulate cofactor balance.
Cofactor balance plays an important role in producing enzymes, pharmaceuticals and chemicals. To meet the demand of industrial production, microbes should maintain a maximal carbon flux towards target metabolites without fluctuations in cofactor. We reviewed the physiological function of cofactor and discussed detailed strategies to manipulate cofactor balance through biochemical engineering and metabolic engineering. Furthermore, we indicated future research needs to further regulate cofactor balance.
引文
[1]Heux S,Cachon R,Dequin S.Cofactor engineering in Saccharomyces cerevisiae:expression of a H2O-forming NADH oxidase and impact on redox metabolism.Metab Eng,2006,8(4):303-314.
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[3]Shen CR,Lan EI,Dekishima Y,et al.Driving forces enable high-titer anaerobic 1-butanol synthesis in Escherichia coli.Appl Environ Microbiol,2011,77(9):2905-2915.
[4]Bera AK,Ho NWY,Khan A,et al.A genetic overhaul of Saccharomyces cerevisiae 424A(LNH-ST)to improve xylose fermentation.J Ind Microbiol Biotechnol,2011,38(5):617-626.
[5]Qin Y,Dong ZY,Liu LM,et al.Manipulation of NADH metabolism in industrial strains.Chin JBiotech,2009,25(2):161-169(in Chinese).秦义,董志姚,刘立明,等.工业微生物中NADH的代谢调控.生物工程学报,2009,25(2):161-169.
[6]Wang YP,San KY,Bennett GN.Cofactor engineering for advancing chemical biotechnology.Curr Opin Biotechnol,2013,24(6):994-999.
[7]Vadali RV,Bennett GN,San KY.Cofactor engineering of intracellular Co A/acetyl-Co A and its effect on metabolic flux redistribution in Escherichia coli.Metab Eng,2004,6(2):133-139.
[8]Zhou JW,Liu LM,Shi ZP,et al.ATP in current biotechnology:regulation,applications and perspectives.Biotechnol Adv,2009,27(1):94-101.
[9]Liu LM,Li Y,Shi ZP,et al.Enhancement of pyruvate productivity in Torulopsis glabrata:increase of NAD+availability.J Biotechnol,2006,126(2):173-185.
[10]La Piana G,Marzulli D,Gorgoglione V,et al.Porin and cytochrome oxidase containing contact sites involved in the oxidation of cytosolic NADH.Arch Biochem Biophys,2005,436(1):91-100.
[11]Lin SJ,Ford E,Haigis M,et al.Calorie restriction extends yeast life span by lowering the level of NADH.Genes Dev,2004,18(1):12-16.
[12]Domergue R,Casta?o I,De Las Pe?as A,et al.Nicotinic acid limitation regulates silencing of Candida adhesins during UTI.Science,2005,308(5723):866-870.
[13]Clomburg JM,Gonzalez R.Anaerobic fermentation of glycerol:a platform for renewable fuels and chemicals.Trends Biotechnol,2013,31(1):20-28.
[14]Neidhardt FC.Escherichia coli and Salmonella:Cellular and Molecular Biology.2nd ed.Amer:Amer Society for Microbiology Press,1996:1458-1496.
[15]Murarka A,Dharmadi Y,Yazdani SS,et al.Fermentative utilization of glycerol by Escherichia coli and its implications for the production of fuels and chemicals.Appl Environ Microbiol,2008,74(4):1124-1135.
[16]Wahlbom CF,Hahn-H?gerdal B.Furfural,5-hydroxymethyl furfural,and acetoin act as external electron acceptors during anaerobic fermentation of xylose in recombinant Saccharomyces cerevisiae.Biotechnol Bioeng,2002,78(2):172-178.
[17]Wu H,Li ZM,Zhou L,et al.Improved succinic acid production in the anaerobic culture of an Escherichia coli pfl B ldh A double mutant as a result of enhanced anaplerotic activities in the preceding aerobic culture.Appl Environ Microbiol,2007,73(24):7837-7843.
[18]Wu H,Li ZM,Zhou L,et al.Improved anaerobic succinic acid production by Escherichia coli NZN111 aerobically grown on glyconeogenic carbon sources.J Biotechnol,2008,136(S):S417.
[19]Diano A,Bekker-Jensen S,Dynesen J,et al.Polyol synthesis in Aspergillus niger:influence of oxygen availability,carbon and nitrogen sources on the metabolism.Biotechnol Bioeng,2006,94(5):899-908.
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[21]Menzel K,Ahrens K,Zeng A,et al.Kinetic,dynamic,and pathway studies of glycerol metabolism by Klebsiella pneumoniae in anaerobic continuous culture:IV.enzymes and fluxes of pyruvate metabolism.Biotechnol Bioeng,1998,60(5):617-626.
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[23]Du C,Yan H,Zhang Y,et al.Use of oxidoreduction potential as an indicator to regulate 1,3-propanediol fermentation by Klebsiella pneumoniae.Appl Microbiol Biotechnol,2006,69(5):554-563.
[24]Khosla C,Keasling JD.Metabolic engineering for drug discovery and development.Nat Rev Drug Discov,2003,2(12):1019-1025.
[25]Blazeck J,Alper HS.Promoter engineering:recent advances in controlling transcription at the most fundamental level.Biotechnol J,2013,8(1):46-58.
[26]Na D,Kim TY,Lee SY.Construction and optimization of synthetic pathways in metabolic engineering.Curr Opin Microbiol,2010,13(3):363-370.
[27]Pfleger BF,Pitera DJ,Smolke CD,et al.Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes.Nat Biotechnol,2006,24(8):1027-1032.
[28]Salis HM,Mirsky EA,Voigt CA.Automated design of synthetic ribosome binding sites to control protein expression.Nat Biotechnol,2009,27(10):946-950.
[29]Zhang FZ,Carothers JM,Keasling JD.Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids.Nat Biotechnol,2012,30(4):354-359.
[30]Xu P,Gu Q,Wang WY,et al.Modular optimization of multi-gene pathways for fatty acids production in E.coli.Nat Commun,2013,4:1409.
[31]Foo JL,Ching CB,Chang MW,et al.The imminent role of protein engineering in synthetic biology.Biotechnol Adv,2012,30(3):541-549.
[32]Li YG.Beyond protein engineering:its applications in synthetic biology.Enz Eng,2012,1(2):e103.
[33]Hoelsch K,Sührer I,Heusel M,et al.Engineering of formate dehydrogenase:synergistic effect of mutations affecting cofactor specificity and chemical stability.Appl Microbiol Biotechnol,2013,97(6):2473-2481.
[34]Ji DB,Wang L,Hou SH,et al.Creation of bioorthogonal redox systems depending on nicotinamide flucytosine dinucleotide.J Am Chem Soc,2011,133(51):20857-20862.
[35]Liu X,Bastian S,Snow CD,et al.Structure-guided engineering of Lactococcus lactis alcohol dehydrogenase Ll Adh A for improved conversion of isobutyraldehyde to isobutanol.J Biotechnol,2013,164(2):188-195.
[36]Paladini DH,Musumeci MA,Carrillo N,et al.Induced fit and equilibrium dynamics for high catalytic efficiency in ferredoxin-NADP(H)reductases.Biochemistry,2009,48(24):5760-5768.
[37]Zhang KC,Li H,Cho KM,et al.Expanding metabolism for total biosynthesis of the nonnatural amino acid L-homoalanine.Proc Natl Acad Sci USA,2010,107(14):6234-6239.
[38]Zhou YJ,Gao W,Rong QX,et al.Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production.J Am Chem Soc,2012,134(6):3234-3241.
[39]Banta S,Swanson BA,Wu S,et al.Optimizing an artificial metabolic pathway:engineering the cofactor specificity of Corynebacterium2,5-diketo-D-gluconic acid reductase for use in vitamin C biosynthesis.Biochemistry,2002,41(20):6226-6236.
[40]Chen Z,Wilmanns M,Zeng AP.Structural synthetic biotechnology:from molecular structure to predictable design for industrial strain development.Trends Biotechnol,2010,28(10):534-542.
[41]Conrado RJ,Wu GC,Boock JT,et al.DNA-guided assembly of biosynthetic pathways promotes improved catalytic efficiency.Nucleic Acids Res,2012,40(4):1879-1889.
[42]Delebecque CJ,Lindner AB,Silver PA,et al.Organization of intracellular reactions with rationally designed RNA assemblies.Science,2011,333(6041):470-474.
[43]Dueber JE,Wu GC,Malmirchegini GR,et al.Synthetic protein scaffolds provide modular control over metabolic flux.Nat Biotechnol,2009,27(8):753-759.
[44]Baek JM,Mazumdar S,Lee SW,et al.Butyrate production in engineered Escherichia coli with synthetic scaffolds.Biotechnol Bioeng,2013,110(10):2790-2794.
[45]Lim JH,Seo SW,Kim SY,et al.Refactoring redox cofactor regeneration for high-yield biocatalysis of glucose to butyric acid in Escherichia coli.Bioresour Technol,2013,135:568-573.
[46]Agapakis CM,Boyle PM,Silver PA.Natural strategies for the spatial optimization of metabolism in synthetic biology.Nat Chem Biol,2012,8(6):527-535.
[47]Lee JW,Na D,Park JM,et al.Systems metabolic engineering of microorganisms for natural and non-natural chemicals.Nat Chem Biol,2012,8(6):536-546.
[48]Jang YS,Park JM,Choi S,et al.Engineering of microorganisms for the production of biofuels and perspectives based on systems metabolic engineering approaches.Biotechnol Adv,2012,30(5):989-1000.
[49]Hibi M,Yukitomo H,Ito M,et al.Improvement of NADPH-dependent bioconversion by transcriptomebased molecular breeding.Appl Environ Microbiol,2007,73(23):7657-7663.
[50]Yim H,Haselbeck R,Niu W,et al.Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol.Nat Chem Biol,2011,7(7):445-452.
[51]Guo TT,Kong J,Zhang L,et al.Fine tuning of the lactate and diacetyl production through promoter engineering in Lactococcus lactis.PLo S ONE,2012,7(4):e36296.
[52]Vemuri GN,Eiteman MA,Mc Ewen JE,et al.Increasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae.Proc Natl Acad Sci USA,2007,104(7):2402-2407.
[53]Zou YZ,Zhang HJ,Brunzelle JS,et al.Crystal structures of phosphite dehydrogenase provide insights into nicotinamide cofactor regeneration.Biochemistry,2012,51(21):4263-4270.
[54]Lee WH,Kim JW,Park EH,et al.Effects of NADHkinase on NADPH-dependent biotransformation processes in Escherichia coli.Appl Microbiol Biotechnol,2013,97(4):1561-1569.
[55]Jan J,Martinez I,Wang YP,et al.Metabolic engineering and transhydrogenase effects on NADPH availability in Escherichia coli.Biotechnol Prog,2013,29(5):1124-1130.
[56]Sánchez AM,Andrews J,Hussein I,et al.Effect of overexpression of a soluble pyridine nucleotide transhydrogenase(Udh A)on the production of poly(3-hydroxybutyrate)in Escherichia coli.Biotechnol Prog,2006,22(2):420-425.
[57]Hou J,Lages NF,Oldiges M,et al.Metabolic impact of redox cofactor perturbations in Saccharomyces cerevisiae.Metab Eng,2009,11(4/5):253-261.
[2]de Graef MR,Alexeeva S,Snoep JL,et al.The steady-state internal redox state(NADH/NAD)reflects the external redox state and is correlated with catabolic adaptation in Escherichia coli.JBacteriol,1999,181(8):2351-2357.
[3]Shen CR,Lan EI,Dekishima Y,et al.Driving forces enable high-titer anaerobic 1-butanol synthesis in Escherichia coli.Appl Environ Microbiol,2011,77(9):2905-2915.
[4]Bera AK,Ho NWY,Khan A,et al.A genetic overhaul of Saccharomyces cerevisiae 424A(LNH-ST)to improve xylose fermentation.J Ind Microbiol Biotechnol,2011,38(5):617-626.
[5]Qin Y,Dong ZY,Liu LM,et al.Manipulation of NADH metabolism in industrial strains.Chin JBiotech,2009,25(2):161-169(in Chinese).秦义,董志姚,刘立明,等.工业微生物中NADH的代谢调控.生物工程学报,2009,25(2):161-169.
[6]Wang YP,San KY,Bennett GN.Cofactor engineering for advancing chemical biotechnology.Curr Opin Biotechnol,2013,24(6):994-999.
[7]Vadali RV,Bennett GN,San KY.Cofactor engineering of intracellular Co A/acetyl-Co A and its effect on metabolic flux redistribution in Escherichia coli.Metab Eng,2004,6(2):133-139.
[8]Zhou JW,Liu LM,Shi ZP,et al.ATP in current biotechnology:regulation,applications and perspectives.Biotechnol Adv,2009,27(1):94-101.
[9]Liu LM,Li Y,Shi ZP,et al.Enhancement of pyruvate productivity in Torulopsis glabrata:increase of NAD+availability.J Biotechnol,2006,126(2):173-185.
[10]La Piana G,Marzulli D,Gorgoglione V,et al.Porin and cytochrome oxidase containing contact sites involved in the oxidation of cytosolic NADH.Arch Biochem Biophys,2005,436(1):91-100.
[11]Lin SJ,Ford E,Haigis M,et al.Calorie restriction extends yeast life span by lowering the level of NADH.Genes Dev,2004,18(1):12-16.
[12]Domergue R,Casta?o I,De Las Pe?as A,et al.Nicotinic acid limitation regulates silencing of Candida adhesins during UTI.Science,2005,308(5723):866-870.
[13]Clomburg JM,Gonzalez R.Anaerobic fermentation of glycerol:a platform for renewable fuels and chemicals.Trends Biotechnol,2013,31(1):20-28.
[14]Neidhardt FC.Escherichia coli and Salmonella:Cellular and Molecular Biology.2nd ed.Amer:Amer Society for Microbiology Press,1996:1458-1496.
[15]Murarka A,Dharmadi Y,Yazdani SS,et al.Fermentative utilization of glycerol by Escherichia coli and its implications for the production of fuels and chemicals.Appl Environ Microbiol,2008,74(4):1124-1135.
[16]Wahlbom CF,Hahn-H?gerdal B.Furfural,5-hydroxymethyl furfural,and acetoin act as external electron acceptors during anaerobic fermentation of xylose in recombinant Saccharomyces cerevisiae.Biotechnol Bioeng,2002,78(2):172-178.
[17]Wu H,Li ZM,Zhou L,et al.Improved succinic acid production in the anaerobic culture of an Escherichia coli pfl B ldh A double mutant as a result of enhanced anaplerotic activities in the preceding aerobic culture.Appl Environ Microbiol,2007,73(24):7837-7843.
[18]Wu H,Li ZM,Zhou L,et al.Improved anaerobic succinic acid production by Escherichia coli NZN111 aerobically grown on glyconeogenic carbon sources.J Biotechnol,2008,136(S):S417.
[19]Diano A,Bekker-Jensen S,Dynesen J,et al.Polyol synthesis in Aspergillus niger:influence of oxygen availability,carbon and nitrogen sources on the metabolism.Biotechnol Bioeng,2006,94(5):899-908.
[20]Elliott SJ,Léger C,Pershad HR,et al.Detection and interpretation of redox potential optima in the catalytic activity of enzymes.Biochim Biophys Acta,2002,1555(1/3):54-59.
[21]Menzel K,Ahrens K,Zeng A,et al.Kinetic,dynamic,and pathway studies of glycerol metabolism by Klebsiella pneumoniae in anaerobic continuous culture:IV.enzymes and fluxes of pyruvate metabolism.Biotechnol Bioeng,1998,60(5):617-626.
[22]Riondet C,Cachon R,WachéY,et al.Extracellular oxidoreduction potential modifies carbon and electron flow in Escherichia coli.J Bacteriol,2000,182(3):620-626.
[23]Du C,Yan H,Zhang Y,et al.Use of oxidoreduction potential as an indicator to regulate 1,3-propanediol fermentation by Klebsiella pneumoniae.Appl Microbiol Biotechnol,2006,69(5):554-563.
[24]Khosla C,Keasling JD.Metabolic engineering for drug discovery and development.Nat Rev Drug Discov,2003,2(12):1019-1025.
[25]Blazeck J,Alper HS.Promoter engineering:recent advances in controlling transcription at the most fundamental level.Biotechnol J,2013,8(1):46-58.
[26]Na D,Kim TY,Lee SY.Construction and optimization of synthetic pathways in metabolic engineering.Curr Opin Microbiol,2010,13(3):363-370.
[27]Pfleger BF,Pitera DJ,Smolke CD,et al.Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes.Nat Biotechnol,2006,24(8):1027-1032.
[28]Salis HM,Mirsky EA,Voigt CA.Automated design of synthetic ribosome binding sites to control protein expression.Nat Biotechnol,2009,27(10):946-950.
[29]Zhang FZ,Carothers JM,Keasling JD.Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids.Nat Biotechnol,2012,30(4):354-359.
[30]Xu P,Gu Q,Wang WY,et al.Modular optimization of multi-gene pathways for fatty acids production in E.coli.Nat Commun,2013,4:1409.
[31]Foo JL,Ching CB,Chang MW,et al.The imminent role of protein engineering in synthetic biology.Biotechnol Adv,2012,30(3):541-549.
[32]Li YG.Beyond protein engineering:its applications in synthetic biology.Enz Eng,2012,1(2):e103.
[33]Hoelsch K,Sührer I,Heusel M,et al.Engineering of formate dehydrogenase:synergistic effect of mutations affecting cofactor specificity and chemical stability.Appl Microbiol Biotechnol,2013,97(6):2473-2481.
[34]Ji DB,Wang L,Hou SH,et al.Creation of bioorthogonal redox systems depending on nicotinamide flucytosine dinucleotide.J Am Chem Soc,2011,133(51):20857-20862.
[35]Liu X,Bastian S,Snow CD,et al.Structure-guided engineering of Lactococcus lactis alcohol dehydrogenase Ll Adh A for improved conversion of isobutyraldehyde to isobutanol.J Biotechnol,2013,164(2):188-195.
[36]Paladini DH,Musumeci MA,Carrillo N,et al.Induced fit and equilibrium dynamics for high catalytic efficiency in ferredoxin-NADP(H)reductases.Biochemistry,2009,48(24):5760-5768.
[37]Zhang KC,Li H,Cho KM,et al.Expanding metabolism for total biosynthesis of the nonnatural amino acid L-homoalanine.Proc Natl Acad Sci USA,2010,107(14):6234-6239.
[38]Zhou YJ,Gao W,Rong QX,et al.Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production.J Am Chem Soc,2012,134(6):3234-3241.
[39]Banta S,Swanson BA,Wu S,et al.Optimizing an artificial metabolic pathway:engineering the cofactor specificity of Corynebacterium2,5-diketo-D-gluconic acid reductase for use in vitamin C biosynthesis.Biochemistry,2002,41(20):6226-6236.
[40]Chen Z,Wilmanns M,Zeng AP.Structural synthetic biotechnology:from molecular structure to predictable design for industrial strain development.Trends Biotechnol,2010,28(10):534-542.
[41]Conrado RJ,Wu GC,Boock JT,et al.DNA-guided assembly of biosynthetic pathways promotes improved catalytic efficiency.Nucleic Acids Res,2012,40(4):1879-1889.
[42]Delebecque CJ,Lindner AB,Silver PA,et al.Organization of intracellular reactions with rationally designed RNA assemblies.Science,2011,333(6041):470-474.
[43]Dueber JE,Wu GC,Malmirchegini GR,et al.Synthetic protein scaffolds provide modular control over metabolic flux.Nat Biotechnol,2009,27(8):753-759.
[44]Baek JM,Mazumdar S,Lee SW,et al.Butyrate production in engineered Escherichia coli with synthetic scaffolds.Biotechnol Bioeng,2013,110(10):2790-2794.
[45]Lim JH,Seo SW,Kim SY,et al.Refactoring redox cofactor regeneration for high-yield biocatalysis of glucose to butyric acid in Escherichia coli.Bioresour Technol,2013,135:568-573.
[46]Agapakis CM,Boyle PM,Silver PA.Natural strategies for the spatial optimization of metabolism in synthetic biology.Nat Chem Biol,2012,8(6):527-535.
[47]Lee JW,Na D,Park JM,et al.Systems metabolic engineering of microorganisms for natural and non-natural chemicals.Nat Chem Biol,2012,8(6):536-546.
[48]Jang YS,Park JM,Choi S,et al.Engineering of microorganisms for the production of biofuels and perspectives based on systems metabolic engineering approaches.Biotechnol Adv,2012,30(5):989-1000.
[49]Hibi M,Yukitomo H,Ito M,et al.Improvement of NADPH-dependent bioconversion by transcriptomebased molecular breeding.Appl Environ Microbiol,2007,73(23):7657-7663.
[50]Yim H,Haselbeck R,Niu W,et al.Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol.Nat Chem Biol,2011,7(7):445-452.
[51]Guo TT,Kong J,Zhang L,et al.Fine tuning of the lactate and diacetyl production through promoter engineering in Lactococcus lactis.PLo S ONE,2012,7(4):e36296.
[52]Vemuri GN,Eiteman MA,Mc Ewen JE,et al.Increasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae.Proc Natl Acad Sci USA,2007,104(7):2402-2407.
[53]Zou YZ,Zhang HJ,Brunzelle JS,et al.Crystal structures of phosphite dehydrogenase provide insights into nicotinamide cofactor regeneration.Biochemistry,2012,51(21):4263-4270.
[54]Lee WH,Kim JW,Park EH,et al.Effects of NADHkinase on NADPH-dependent biotransformation processes in Escherichia coli.Appl Microbiol Biotechnol,2013,97(4):1561-1569.
[55]Jan J,Martinez I,Wang YP,et al.Metabolic engineering and transhydrogenase effects on NADPH availability in Escherichia coli.Biotechnol Prog,2013,29(5):1124-1130.
[56]Sánchez AM,Andrews J,Hussein I,et al.Effect of overexpression of a soluble pyridine nucleotide transhydrogenase(Udh A)on the production of poly(3-hydroxybutyrate)in Escherichia coli.Biotechnol Prog,2006,22(2):420-425.
[57]Hou J,Lages NF,Oldiges M,et al.Metabolic impact of redox cofactor perturbations in Saccharomyces cerevisiae.Metab Eng,2009,11(4/5):253-261.