Please wait a minute...

中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2017, Vol. 37 Issue (5): 118-125    DOI: 10.13523/j.cb.20170515
综述     
微生物发酵法生产高分子量透明质酸的研究进展
郜娇娇, 杨树林
南京理工大学环境与生物工程学院 南京 210094
Advances in the Production of High Molecular Weight Hyaluronic Acid by Microbial Fermentation
GAO Jiao-jiao, YANG Shu-lin
School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210094, China
 全文: PDF(681 KB)   HTML
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。
关键词： 透明质酸;  微生物发酵法;  分子量    
Abstract:

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.
Key words: Molecular weight    Microbial fermentation    Hyaluronic acid
收稿日期: 2017-01-16 出版日期: 2017-05-25
ZTFLH:  Q815  
基金资助:

国家“863”计划资助项目（2014AA022107）
通讯作者: 杨树林     E-mail: yshulin@njust.edu.cn
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　

引用本文:

郜娇娇, 杨树林. 微生物发酵法生产高分子量透明质酸的研究进展[J]. 中国生物工程杂志, 2017, 37(5): 118-125.

GAO Jiao-jiao, YANG Shu-lin. Advances in the Production of High Molecular Weight Hyaluronic Acid by Microbial Fermentation. China Biotechnology, 2017, 37(5): 118-125.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20170515    或    https://manu60.magtech.com.cn/biotech/CN/Y2017/V37/I5/118

[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 Acid-Producing 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] DeAngelis 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, DeAngelis P L. Hyaluronan synthases:a decade-plus of novel glycosyltransferases. J Biol Chem, 2007, 282(51):36777-36781.
[7] Jing W, DeAngelis P L. Synchronized chemoenzymatic synthesis of monodisperse hyaluronan polymers. J Biol Chem, 2004, 279(40):42345-42349.
[8] Pummill P E, Achyuthan A M, DeAngelis P L. Enzymological characterization of recombinant xenopus DG42, a vertebrate hyaluronan synthase. J Biol Chem, 1998, 273(9):4976-4981.
[9] Pummill P E, DeAngelis 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 BiolChem, 2006, 281(17):11755-11760.
[16] Schulz T, Schumacher U, Prehm P. Hyaluronan export by the ABC transporter MRP5and its modulation by in tracellular cGMP. 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 3is 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 SH0201for 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 UDP-glucose 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 P170 expression 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.
[1] 段思腾,李光然,马义勇,邱裕佳,李宇,王伟. 负载NGF的可注射壳聚糖透明质酸水凝胶材料理化性能及生物相容性研究[J]. 中国生物工程杂志, 2018, 38(4): 70-77.
[2] 郜娇娇, 杨树林. 基因工程技术优化透明质酸生产的研究进展[J]. 中国生物工程杂志, 2017, 37(8): 72-77.
[3] 陈国强, 吴文涛, 王纪明, 廖韦红, 张海波, 咸漠, 雷廷宙, 魏玉西. 出芽短梗霉A5产胞外多糖发酵条件的优化及产物结构鉴定[J]. 中国生物工程杂志, 2017, 37(2): 54-62.
[4] 张清芳, 刘如明, 肖建辉. 透明质酸在间充质干细胞向软骨细胞分化中的应用[J]. 中国生物工程杂志, 2016, 36(6): 92-99.
[5] 陈建澍, 王婧茜, 易喻, 龚海平, 应国清. 透明质酸及其衍生物研究进展[J]. 中国生物工程杂志, 2015, 35(2): 111-118.
[6] 蒋延超, 蒋世云, 傅凤鸣, 黄凯, 康星欣, 徐丹. 透明质酸生物合成途径及基因工程研究进展[J]. 中国生物工程杂志, 2015, 35(1): 104-110.
[7] 朱怡然, 范雪荣, 王强, 陈忍忍, 余圆圆, 袁久刚. 右旋糖酐对Savinase蛋白酶的化学修饰及酶学性质研究[J]. 中国生物工程杂志, 2011, 31(10): 45-49.
[8] 赵志军, 陈晟, 吴丹, 吴敬, 陈坚. 微生物发酵法生产L-色氨酸的代谢工程研究[J]. 中国生物工程杂志, 2011, 31(06): 135-141.
[9] 文程 于慧敏 孙云鹏 王颖 沈忠耀. 高效测定发酵液中透明质酸含量的改良CTAB浊度法[J]. 中国生物工程杂志, 2010, 30(02): 89-93.
[10] 叶春江,张颖,刘发珍,李强. DNA分子量标准制备技术：方法与进展[J]. 中国生物工程杂志, 2009, 29(08): 119-123.
[11] 田平芳,曲凯,谭天伟. 链球菌生物合成透明质酸的分子机理与基因工程菌构建进展[J]. 中国生物工程杂志, 2008, 28(4): 98-102.
[12] 金晶,姚俊,徐虹,许琳. 枯草杆菌NX-2聚谷氨酸解聚酶的克隆表达及其降解性质研究[J]. 中国生物工程杂志, 2007, 27(5): 34-38.
[13] 张金锐,刘勇,林刚,何光源. 小麦高分子量麦谷蛋白亚基序列及其结构与加工品质的关系[J]. 中国生物工程杂志, 2006, 26(08): 103-110.
[14] 戚楠,马清钧. 长效重组蛋白药物的研究进展[J]. 中国生物工程杂志, 2006, 26(02): 79-82.
[15] 尹建云,张学松,孟海华,梁世中. 葡萄糖对微生物合成3-羟基丁酸和3-羟基己酸共聚酯（PHBHHX）分子量的影响[J]. 中国生物工程杂志, 2006, 26(0): 136-138.
主管：中国科学院 　主办：中国科学院文献情报中心 　中国生物技术发展中心 　中国生物工程学会