微生物发酵法生产高分子量透明质酸的研究进展
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摘要
透明质酸是一种线性大分子黏多糖,分子量定义其流变性能,影响生理反应,并决定合适的用途。传统研究通过优化发酵提高透明质酸的产量已取得显著成效,近年来,研究重点逐渐转向如何提高透明质酸产品的分子量。目前,高分子量透明质酸具有良好的黏弹性、保湿性、黏附性,在医药中的应用是中、低分子量透明质酸不可替代的。概述了透明质酸分子量的调控机制,以及利用微生物发酵法生产高分子量透明质酸的研究进展,并对其发展方向进行了展望。
Hyaluronic acid is a linear high molecular weight mucopolysaccharide with its molecular weight determining its rheological properties, physiological role and applications. Traditional studies have made significant efforts to improve the yield of hyaluronic acid by optimizing the fermentation. In recent years,the research focus has gradually shifted to how to improve the molecular weight of hyaluronic acid products. At present,the high molecular weight hyaluronic acid has good viscoelasticity,moisture retention and adhesion,and the application of the medicine is irreplaceable by the middle or low molecular weight hyaluronic acid. The mechanism of hyaluronic acid molecular weight regulation and the research progress of the production of high molecular weight hyaluronic acid by microbial fermentation were reviewed,and its development direction was prospected.
Hyaluronic acid is a linear high molecular weight mucopolysaccharide with its molecular weight determining its rheological properties, physiological role and applications. Traditional studies have made significant efforts to improve the yield of hyaluronic acid by optimizing the fermentation. In recent years,the research focus has gradually shifted to how to improve the molecular weight of hyaluronic acid products. At present,the high molecular weight hyaluronic acid has good viscoelasticity,moisture retention and adhesion,and the application of the medicine is irreplaceable by the middle or low molecular weight hyaluronic acid. The mechanism of hyaluronic acid molecular weight regulation and the research progress of the production of high molecular weight hyaluronic acid by microbial fermentation were reviewed,and its development direction was prospected.
引文
[1]Chong B F,Blank L M,Mclaughlin R,et al.Microbial hyaluronic acid production.Appl Microbiol Biotechnol,2005,66(4):341-351.
[2]张云开.透明质酸生产菌代谢工程研究.南宁:广西大学,生命科学与技术学院,2002.Zhang Y K.Metabolic Engineering Research of Hyaluronic AcidProducing Bacterium Streptococcus equi.Nanning:Guangxi University,College of Life Science and Technology,2002.
[3]张延良.发酵法生产医用级透明质酸的工艺研究.上海:上海交通大学,生命科学技术学院,2010.Zhang Y L.Study on the Technology of Producing Medical Grade Hyaluronic Acid by Fermentation.Shanghai:Shanghai Jiaotong University,College of Life Science and Technology,2010.
[4]生举正,凌沛学,王凤山.透明质酸生物合成的研究进展.中国生化药物杂志,2009,30(2):135-138.Sheng J Z,Ling P X,Wang F S.Research advances of hyaluronic acid biosynthesis.Chinese Journal of Biochemical Pharmaceutics,2009,30(2):135-138.
[5]De Angelis P L.Hyaluronan synthases:fascinating glycosyltransferases from vertebrates,bacterial pathogens,and algal viruses.Cell Mol Life Sci,1999,56(7-8):670-682.
[6]Weigel P H,De Angelis P L.Hyaluronan synthases:a decadeplus of novel glycosyltransferases.J Biol Chem,2007,282(51):36777-36781.
[7]Jing W,De Angelis P L.Synchronized chemoenzymatic synthesis of monodisperse hyaluronan polymers.J Biol Chem,2004,279(40):42345-42349.
[8]Pummill P E,Achyuthan A M,De Angelis P L.Enzymological characterization of recombinant xenopus DG42,a vertebrate hyaluronan synthase.J Biol Chem,1998,273(9):4976-4981.
[9]Pummill P E,De Angelis P L.Alteration of polysaccharide size distribution of a vertebrate hyaluronan synthase by mutation.J Biol Chem,2003,278(22):19808-19814.
[10]Sheng J,Ling P,Zhu X,et al.Use of induction promoters to regulate hyaluronan synthase and UDP-glucose-6-dehydrogenase of Streptococcus zooepidemicus expression in Lactococcus lactis:a case study of the regulation mechanism of hyaluronic acid polymer.J Appl Microbiol,2009,107(1):136-144.
[11]Swaminathan J,Ramachandran K B.Influence of competing metabolic processes on the molecular weight of hyaluronic acid synthesized by Streptococcus zooepidemicus.Biochemical Engineering Journal,2010,48(2):148-158.
[12]Chen W,Marcellin E,Hung J,et al.Hyaluronan molecular weight is controlled by UDP-N-acetylglucosamine concentration in Streptococcus zooepidemicus.J Biol Chem,2009,284(27):18007-18014.
[13]Jokela T A,Jauhiainen M,Auriola S,et al.Mannose inhibits hyaluronan synthesis by down-regulation of the cellular pool of UDP-N-acetylhexosamines.J Biol Chem,2008,283(12):7666-7673.
[14]Chen W,Marcellin E,Steen J A,et al.The role of hyaluronic acid precursor concentrations in molecular weight control in Streptococcus zooepidemicus.Mol Biotechnol,2013,56(2):147-156.
[15]Kumari K,Baggenstoss B A,Parker A L,et al.Mutation of two intram embrane polar residues conserved with in the hyaluronan synthase family alters hyaluronan product size.J Biol Chem,2006,281(17):11755-11760.
[16]Schulz T,Schumacher U,Prehm P.Hyaluronan export by the ABC transporter MRP5 and its modulation by in tracellular c GMP.J Biol Chem,2007,282(29):20999-21004.
[17]Medinal A P,Lin J L,Weigel P H.Hyaluronan synthase mediates dye translocation across liposomal membranes.BMC Biochem,2012,13(1):2-10.
[18]Vigetti D,Viola M,Karousou E,et al.Metabolic control of hyaluronan synthases.Matrix Biology,2014,35:8-13.
[19]Weigel P H.Functional characteristics and catalytic mechanisms of the bacterial hyaluronan synthases.IUBMB Life,2002,54(4):201-211.
[20]Goentzel B J,Weigel P H,Steinberg R A.Recombinant human hyaluronan synthase 3 is phosphorylated in mammalian cells.Biochem J,2006,396(2):347-354.
[21]Rilla K,Siiskonen H,Spicer A P,et al.Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity.J Biol Chem,2005,280(36):31890-31897.
[22]冯建成,冯浩,牛成,等.高分子量透明质酸生产菌SH0201的诱变选育.中国酿造,2011,30(3):45-47.Feng J C,Feng H,Niu C,et al.Mutation of SH0201 for high molecular weight hyaluronic acid production.China Brewing,2011,30(3):45-47.
[23]张容鹄,冯建成,张剑韵,等.高分子量透明质酸产生菌选育及发酵条件优化.中国酿造,2008,27(19):17-21.Zhang R H,Feng J C,Zhang J Y,et al.Screening of Streptococcus equi strain for the production of hyaluronic acid with high molecular weight and optimization of related fermentation conditions.China Brewing,2008,27(19):17-21.
[24]陈奕涵,钱悦,侯永泰,等.复合诱变选育大分子量透明质酸高产菌株.中国酿造,2012,31(9):98-101.Chen Y H,Qian Y,Hou Y T,et al.Compound mutation screening strain for molecular weight and high-yield hyaluronic acid.China Brewing,2012,31(9):98-101.
[25]刘金龙,赵国群,李志敏,等.培养条件对Streptococcus equisimilis合成透明质酸相对分子质量的影响.食品与生物技术学报,2015,34(2):209-214.Liu J L,Zhao G Q,Li Z M,et al.Effect of culture condition on the molecular weight of hyaluronic acid synthesized by Streptococcus equisimilis,Journal of Food Science and Biotechnology,2015,34(2):209-214.
[26]Jagannath S,Ramachandran K B.Influence of competing metabolic processes on the molecular weight of hyaluronic acid synthesized by Streptococcus zooepidemicus.Biochemical Engineering Journal,2010,48(2):148-158.
[27]Kim J H,Yoo S J,Oh D K,et al.Selection of a Streptococcus equi mutant and optimization of culture conditions for the production of high molecular weight hyaluronic acid.Enzyme and Microbial Technology,1996,19(6):440-445.
[28]成霞,刘登如,陈坚,等.高产量、高分子量透明质酸发酵条件优化.过程工程学报,2006,6(5):809-813.Cheng X,Liu D R,Chen J,et al.Optimization of fermentation conditions for high yield and high molecular weight hyaluronic acid.The Chinese Journal of Process Engineering,2006,6(5):809-813.
[29]Armstrong D C,Johns M R.Culture conditions affect the molecular weight properties of hyaluronic acid produced by Streptococcus zooepidemicus.Appl Environ Microbiol,1997,63(7):2759-2764.
[30]Gao H J,Chen J,Du G C,et al.Effect of agitation and mixing on hyaluronic acid production by Streptococcus zooepidemicus.Journal of Chemical Industry and Engineering,2003,54(3):350-356.
[31]Zhang X,Duan X,Tan W.Mechanism for the effect of agitation on the molecular weight of hyaluronic acid produced by Streptococcus zooepidemicus.Food Chemistry,2010,119(4):1643-1646.
[32]凌敏,黄日波,黄鲲,等.马链球菌透明质酸合成酶基因的分子克隆及表达.工业微生物,2003,33(2):4-8.Ling M,Huang R B,Huang K,et al.Cloning and expression of hyaluronan synthase gene from Streptococcus equi.Industrial Microbiology,2003,33(2):4-8.
[33]Widner B,Behr R,Von Dollen S,et al.Hyaluronic acid production in Bacillus subtilis.Appl Environ Microbiol,2005,71(7):3747-3752.
[34]Jeong E,Shim W Y,Kim J H.Metabolic engineering of Pichia pastoris for production of hyaluronic acid with high molecular weight.J Biotechnol,2014,185:28-36.
[35]Yu H,Stephanopoulos G.Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid.Metab Eng,2008,10(1):24-32.
[36]Jia Y N,Zhu J,Chen X F,et al.Metabolic engineering of Bacillus subtilis for the efficient biosynthesis of uniform hyaluronic acid with controlled molecular weights.Bioresour Technol,2013,132:427-431.
[37]Mao Z,Shin H D,Chen R.A recombinant E.coli bioprocess for hyaluronan synthesis.Appl Microbiol Biotechnol,2009,84(1):63-69.
[38]Prasad S B,Jayaraman G,Ramachandran K B.Hyaluronic acid production is enhanced by the additional co-expression of UDPglucose pyrophosphorylase in Lactococcus lactis.Appl Microbiol Biotechnol,2010,86(1):273-283.
[39]Chauhan A S,Badle S S,Ramachandran K B,et al.The P170expression system enhances hyaluronan molecular weight and production in metabolically-engineered Lactococcus lactis.Biochem Eng J,2014,90:73-78.
[40]Hmar R V,Prasad S B,Jayaraman G,et al.Chromosomal integration of hyaluronic acid synthesis(has)genes enhances the molecular weight of hyaluronan produced in Lactococcus lactis.Biotechnol J,2014,9(12):1554-1564.
[41]Mao Z,Chen R R.Recombinant synthesis of hyaluronan by Agrobacterium sp..Biotechnol Prog,2007,23(5):1038-1042.
[42]李志敏.高分子量透明质酸发酵工艺的研究.石家庄:河北科技大学,生命科学与工程学院,2015.Li Z M.Study on fermentation process of high-molecular-weight hyaluronic acid.Shijazhuang:Hebei University of Science and Technology,College of Bioscience&Bioengineering,2015.
[43]Shah M V,Badle S S,Ramachandran K B.Hyaluronic acid production and molecular weight improvement by redirection of carbon flux towards its biosynthesis pathway.Biochemical Engineering Journal,2013,80:53-60.
[44]Cleary P P,Larkin A.Hyaluronic acid capsule:strategy for oxygen resistance in group A streptococci.J Bacteriol,1979,140(3):1090-1097.
[45]管世敏,荣绍丰,陈奕涵.外源氧化胁迫提高透明质酸分子量.中国医药工业杂志,2013,44(1):27-31.Guan S M,Rong S F,Chen Y H.Oxidative stress to increase hyaluranic acid molecule.Chinese Journal of Pharmaceuticals,2013,44(1):27-31.
[46]Lai Z W,Rahim R A,Ariff A B,et al.Biosynthesis of high molecular weight hyaluronic acid by Streptococcus zooepidemicus using oxygen vector and optimum impeller tip speed.Journal of Bioscience and Bioengineering,2012,114(3):286-291.
[2]张云开.透明质酸生产菌代谢工程研究.南宁:广西大学,生命科学与技术学院,2002.Zhang Y K.Metabolic Engineering Research of Hyaluronic AcidProducing Bacterium Streptococcus equi.Nanning:Guangxi University,College of Life Science and Technology,2002.
[3]张延良.发酵法生产医用级透明质酸的工艺研究.上海:上海交通大学,生命科学技术学院,2010.Zhang Y L.Study on the Technology of Producing Medical Grade Hyaluronic Acid by Fermentation.Shanghai:Shanghai Jiaotong University,College of Life Science and Technology,2010.
[4]生举正,凌沛学,王凤山.透明质酸生物合成的研究进展.中国生化药物杂志,2009,30(2):135-138.Sheng J Z,Ling P X,Wang F S.Research advances of hyaluronic acid biosynthesis.Chinese Journal of Biochemical Pharmaceutics,2009,30(2):135-138.
[5]De Angelis P L.Hyaluronan synthases:fascinating glycosyltransferases from vertebrates,bacterial pathogens,and algal viruses.Cell Mol Life Sci,1999,56(7-8):670-682.
[6]Weigel P H,De Angelis P L.Hyaluronan synthases:a decadeplus of novel glycosyltransferases.J Biol Chem,2007,282(51):36777-36781.
[7]Jing W,De Angelis P L.Synchronized chemoenzymatic synthesis of monodisperse hyaluronan polymers.J Biol Chem,2004,279(40):42345-42349.
[8]Pummill P E,Achyuthan A M,De Angelis P L.Enzymological characterization of recombinant xenopus DG42,a vertebrate hyaluronan synthase.J Biol Chem,1998,273(9):4976-4981.
[9]Pummill P E,De Angelis P L.Alteration of polysaccharide size distribution of a vertebrate hyaluronan synthase by mutation.J Biol Chem,2003,278(22):19808-19814.
[10]Sheng J,Ling P,Zhu X,et al.Use of induction promoters to regulate hyaluronan synthase and UDP-glucose-6-dehydrogenase of Streptococcus zooepidemicus expression in Lactococcus lactis:a case study of the regulation mechanism of hyaluronic acid polymer.J Appl Microbiol,2009,107(1):136-144.
[11]Swaminathan J,Ramachandran K B.Influence of competing metabolic processes on the molecular weight of hyaluronic acid synthesized by Streptococcus zooepidemicus.Biochemical Engineering Journal,2010,48(2):148-158.
[12]Chen W,Marcellin E,Hung J,et al.Hyaluronan molecular weight is controlled by UDP-N-acetylglucosamine concentration in Streptococcus zooepidemicus.J Biol Chem,2009,284(27):18007-18014.
[13]Jokela T A,Jauhiainen M,Auriola S,et al.Mannose inhibits hyaluronan synthesis by down-regulation of the cellular pool of UDP-N-acetylhexosamines.J Biol Chem,2008,283(12):7666-7673.
[14]Chen W,Marcellin E,Steen J A,et al.The role of hyaluronic acid precursor concentrations in molecular weight control in Streptococcus zooepidemicus.Mol Biotechnol,2013,56(2):147-156.
[15]Kumari K,Baggenstoss B A,Parker A L,et al.Mutation of two intram embrane polar residues conserved with in the hyaluronan synthase family alters hyaluronan product size.J Biol Chem,2006,281(17):11755-11760.
[16]Schulz T,Schumacher U,Prehm P.Hyaluronan export by the ABC transporter MRP5 and its modulation by in tracellular c GMP.J Biol Chem,2007,282(29):20999-21004.
[17]Medinal A P,Lin J L,Weigel P H.Hyaluronan synthase mediates dye translocation across liposomal membranes.BMC Biochem,2012,13(1):2-10.
[18]Vigetti D,Viola M,Karousou E,et al.Metabolic control of hyaluronan synthases.Matrix Biology,2014,35:8-13.
[19]Weigel P H.Functional characteristics and catalytic mechanisms of the bacterial hyaluronan synthases.IUBMB Life,2002,54(4):201-211.
[20]Goentzel B J,Weigel P H,Steinberg R A.Recombinant human hyaluronan synthase 3 is phosphorylated in mammalian cells.Biochem J,2006,396(2):347-354.
[21]Rilla K,Siiskonen H,Spicer A P,et al.Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity.J Biol Chem,2005,280(36):31890-31897.
[22]冯建成,冯浩,牛成,等.高分子量透明质酸生产菌SH0201的诱变选育.中国酿造,2011,30(3):45-47.Feng J C,Feng H,Niu C,et al.Mutation of SH0201 for high molecular weight hyaluronic acid production.China Brewing,2011,30(3):45-47.
[23]张容鹄,冯建成,张剑韵,等.高分子量透明质酸产生菌选育及发酵条件优化.中国酿造,2008,27(19):17-21.Zhang R H,Feng J C,Zhang J Y,et al.Screening of Streptococcus equi strain for the production of hyaluronic acid with high molecular weight and optimization of related fermentation conditions.China Brewing,2008,27(19):17-21.
[24]陈奕涵,钱悦,侯永泰,等.复合诱变选育大分子量透明质酸高产菌株.中国酿造,2012,31(9):98-101.Chen Y H,Qian Y,Hou Y T,et al.Compound mutation screening strain for molecular weight and high-yield hyaluronic acid.China Brewing,2012,31(9):98-101.
[25]刘金龙,赵国群,李志敏,等.培养条件对Streptococcus equisimilis合成透明质酸相对分子质量的影响.食品与生物技术学报,2015,34(2):209-214.Liu J L,Zhao G Q,Li Z M,et al.Effect of culture condition on the molecular weight of hyaluronic acid synthesized by Streptococcus equisimilis,Journal of Food Science and Biotechnology,2015,34(2):209-214.
[26]Jagannath S,Ramachandran K B.Influence of competing metabolic processes on the molecular weight of hyaluronic acid synthesized by Streptococcus zooepidemicus.Biochemical Engineering Journal,2010,48(2):148-158.
[27]Kim J H,Yoo S J,Oh D K,et al.Selection of a Streptococcus equi mutant and optimization of culture conditions for the production of high molecular weight hyaluronic acid.Enzyme and Microbial Technology,1996,19(6):440-445.
[28]成霞,刘登如,陈坚,等.高产量、高分子量透明质酸发酵条件优化.过程工程学报,2006,6(5):809-813.Cheng X,Liu D R,Chen J,et al.Optimization of fermentation conditions for high yield and high molecular weight hyaluronic acid.The Chinese Journal of Process Engineering,2006,6(5):809-813.
[29]Armstrong D C,Johns M R.Culture conditions affect the molecular weight properties of hyaluronic acid produced by Streptococcus zooepidemicus.Appl Environ Microbiol,1997,63(7):2759-2764.
[30]Gao H J,Chen J,Du G C,et al.Effect of agitation and mixing on hyaluronic acid production by Streptococcus zooepidemicus.Journal of Chemical Industry and Engineering,2003,54(3):350-356.
[31]Zhang X,Duan X,Tan W.Mechanism for the effect of agitation on the molecular weight of hyaluronic acid produced by Streptococcus zooepidemicus.Food Chemistry,2010,119(4):1643-1646.
[32]凌敏,黄日波,黄鲲,等.马链球菌透明质酸合成酶基因的分子克隆及表达.工业微生物,2003,33(2):4-8.Ling M,Huang R B,Huang K,et al.Cloning and expression of hyaluronan synthase gene from Streptococcus equi.Industrial Microbiology,2003,33(2):4-8.
[33]Widner B,Behr R,Von Dollen S,et al.Hyaluronic acid production in Bacillus subtilis.Appl Environ Microbiol,2005,71(7):3747-3752.
[34]Jeong E,Shim W Y,Kim J H.Metabolic engineering of Pichia pastoris for production of hyaluronic acid with high molecular weight.J Biotechnol,2014,185:28-36.
[35]Yu H,Stephanopoulos G.Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid.Metab Eng,2008,10(1):24-32.
[36]Jia Y N,Zhu J,Chen X F,et al.Metabolic engineering of Bacillus subtilis for the efficient biosynthesis of uniform hyaluronic acid with controlled molecular weights.Bioresour Technol,2013,132:427-431.
[37]Mao Z,Shin H D,Chen R.A recombinant E.coli bioprocess for hyaluronan synthesis.Appl Microbiol Biotechnol,2009,84(1):63-69.
[38]Prasad S B,Jayaraman G,Ramachandran K B.Hyaluronic acid production is enhanced by the additional co-expression of UDPglucose pyrophosphorylase in Lactococcus lactis.Appl Microbiol Biotechnol,2010,86(1):273-283.
[39]Chauhan A S,Badle S S,Ramachandran K B,et al.The P170expression system enhances hyaluronan molecular weight and production in metabolically-engineered Lactococcus lactis.Biochem Eng J,2014,90:73-78.
[40]Hmar R V,Prasad S B,Jayaraman G,et al.Chromosomal integration of hyaluronic acid synthesis(has)genes enhances the molecular weight of hyaluronan produced in Lactococcus lactis.Biotechnol J,2014,9(12):1554-1564.
[41]Mao Z,Chen R R.Recombinant synthesis of hyaluronan by Agrobacterium sp..Biotechnol Prog,2007,23(5):1038-1042.
[42]李志敏.高分子量透明质酸发酵工艺的研究.石家庄:河北科技大学,生命科学与工程学院,2015.Li Z M.Study on fermentation process of high-molecular-weight hyaluronic acid.Shijazhuang:Hebei University of Science and Technology,College of Bioscience&Bioengineering,2015.
[43]Shah M V,Badle S S,Ramachandran K B.Hyaluronic acid production and molecular weight improvement by redirection of carbon flux towards its biosynthesis pathway.Biochemical Engineering Journal,2013,80:53-60.
[44]Cleary P P,Larkin A.Hyaluronic acid capsule:strategy for oxygen resistance in group A streptococci.J Bacteriol,1979,140(3):1090-1097.
[45]管世敏,荣绍丰,陈奕涵.外源氧化胁迫提高透明质酸分子量.中国医药工业杂志,2013,44(1):27-31.Guan S M,Rong S F,Chen Y H.Oxidative stress to increase hyaluranic acid molecule.Chinese Journal of Pharmaceuticals,2013,44(1):27-31.
[46]Lai Z W,Rahim R A,Ariff A B,et al.Biosynthesis of high molecular weight hyaluronic acid by Streptococcus zooepidemicus using oxygen vector and optimum impeller tip speed.Journal of Bioscience and Bioengineering,2012,114(3):286-291.