微生物法合成透明质酸的研究及其进展
摘要：透明质酸（Hyaluronic acid)，简称HA。做为一种重要的医学应用材料和化妆品添加原料，HA具有润滑机体关节，调节血管壁的通透性，调节蛋白质，水电解质扩散及运转，促进创伤愈合等优点而被广泛应用到日化材料领域。近年来微生物发酵逐步取代动物组织提取成为生产HA的主要手段，HA的生产方式逐渐发生了更替。而在微生物发酵中由于链球菌属特异性含有HA合成的关键酶-透明质酸合酶（Hyaluronan synthase，简称HAS）及完整的HA代谢途径，因此链球菌成为企业生产HA首选微生物菌种。但链球菌属具有beta;-溶血性等缺点，科研人员常选用物理或化学诱变等方法降低链球菌毒性。与此同时此类诱变方法具有随机性和遗传不稳定性等风险因素，因此成为链球菌作为发酵菌种生产HA的主要限制因素。随着合成生物学的发展，使得利用遗传背景清楚、生物安全性高的底盘细胞生产HA成为可能，枯草芽孢杆菌作为具有除HAS外含所有HA合成代谢途径及关键酶并且被广泛应用于工业生产的菌种，被本课题选定为特定生产透明质酸的对象。本论文对本设计涉及到的透明质酸研究概况、透明质酸生产技术研究概况等方面进行了综述。
关键词：透明质酸；枯草芽孢杆菌；基因工程菌；微生物发酵法
Factory Design with an Annual Output of 15 Tons of Hyaluronic acid
Abstract：As an important medical application materials and cosmetics to add raw materials, HA has the advantages of lubricating body joints, regulating vascular wall permeability, regulating protein, water electrolyte diffusion and operation, and promoting wound healing, etc., so it is widely used in the field of daily chemical materials. To gradually replace the microbial fermentation of animal tissue extraction HA production of the main means in recent years, HA production sources gradually has changed. Streptococcus is the preferred microbial strain for the production of HA, because Streptococcus is a specific enzyme known as hyaluronan synthase (HAS) which is necessary for the production of HA. But the streptococcus has beta;-hemolytic and other shortcomings, researchers often use physical or chemical mutagenesis and other methods to reduce the toxicity of streptococcus. At the same time, such mutagenesis methods are risk factors such as randomness and genetic instability, and thus become the main limiting factor for the production of HA as a fermentative strain. With the development of synthetic biology, making the use of genetic background clear, high biosafety chassis cells to produce HA as possible, Bacillus subtilis as with HAS contains all HA synthetic metabolic pathways and key enzymes and is widely used in industrial production which was selected as the object of producing strain for HA production in this study. This paper summarizes the research situation of HA and the production technology of HA.
Key words: Hyaluronic acid; Bacillus subtilis; Genetically engineered bacteria; Microbial fermentation
1.透明质酸的概述
1.1透明质酸的结构与性质
透明质酸最早在1934年由Meyer等人从牛眼玻璃体中提取分离得到的一种大分子多糖，故又名玻璃酸[1]。透明质酸是由葡糖醛酸和乙酰氨基葡糖为双糖单位组成的直链大分子多糖，相对分子量为10～200万（图1）。透明质酸在水溶液中，其分子高度伸展，并相互缠绕连接，形成连续的网状结构，而水分子则在此网络内通过极性键和氢键与透明质酸分子结合，使得透明质酸就像“分子海绵”一样，能吸收和保持其自身质量1000倍的水分[2]。
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