合成生物学在含氟化合物生产中的应用  

Applications of synthetic biology in the production of fluorinated compounds

作　　者：王高丽 金雪芮 罗云孜 WANG Gaoli;JIN Xuerui;LUO Yunzi(Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering(Ministry of Education),School of Chemical Engineering and Technology,Tianjin University,Tianjin 300072,China;Collaborative Innovation Center of Chemical Science and Engineering(Tianjin),Tianjin University,Tianjin 300072,China)

机构地区：[1]天津大学化工学院,系统生物工程教育部重点实验室,合成生物学前沿科学中心,天津300072 [2]天津大学化学化工协同创新中心,天津300072

出　　处：《合成生物学》2020年第3期358-371,共14页Synthetic Biology Journal

基　　金：天津市自然科学基金(19JCYBJC24200);国家重点研发计划“合成生物学”重点专项(2018YFA0903300)。

摘　　要：将氟原子引入有机化合物分子可以赋予化合物新的功能,使其具有更好的物理化学特性。含氟化合物常被应用于新药研发、医疗诊断等诸多方面,受到合成化学家的广泛关注。但利用有机化学方法合成氟化物往往难以实现氟原子的选择性引入,且含氟试剂成本高,产物分离纯化困难。近年来,合成生物学技术的发展为氟化物的生产提供了新思路。通过发掘链霉菌等微生物中天然的氟化酶,并通过定向进化、理性设计等方法对天然氟化酶进行优化改造,可催化合成特定的C—F键;通过将含氟模块引入天然产物生物合成途径,可合成新型复杂含氟天然产物,如氟化聚酮等。本文归纳总结了利用氟化酶和含氟模块构建氟化物生物合成系统的方法,讨论了合成生物学手段在含氟化合物生产中的重要应用,并从合成生物学的角度展望了优化改造氟化酶和构建新型含氟生物合成系统的未来发展方向。采用合成生物学新策略实现含氟产物的高效生物合成,将有望解决复杂手性含氟化合物的合成问题。Fluorine is the most abundant halogen on the earth.However,the electronegativity of fluorine is extremely strong,which makes the availability of natural fluorine-containing compounds very limited.The introduction of fluorine into organic molecules endows them with new functions and better physicochemical properties,which attracts many synthetic chemists.Since the highly polarized C—F bond is difficult to break,the introduction of fluorine into drug molecules can improve their chemical properties,and thus enhance their metabolic stability for good affinity with target proteins.Nevertheless,it is often difficult to synthesize fluoride compounds with high selectivity by chemical methods.In recent years,the development of synthetic biology has provided new opportunities for the production of fluoride compounds.For example,the natural fluorinase discovered from Streptomyces and its optimized mutants can achieve the formation of C—F bonds.This strategy focuses on using synthetic biology strategies to mine and activate silent gene clusters that synthesize potential fluorinated products,as well as using protein engineering technology to design efficient fluorinase through rational design or directed evolution.On the other hand,the introduction of fluorine-containing building blocks into the natural product biosynthetic pathway can successfully synthesize new fluorinated products.This approach starts with simple fluorinated compounds in the synthesis of fluorine-containing building blocks,and then fluorine can be selectively introduced into biosynthetic pathways for complicated products such as polyketides to form fluorinated natural products.This review summarizes the strategies developed for the production of fluorinated compounds using fluorinase and fluoride biosynthesis systems,and discusses the important applications of synthetic biology methods in the production of fluorinated compounds.We prospect that with the development of synthetic biology techniques,high-efficiency biosynthesis of fluorine-containing prod

关 键 词：氟化物 合成生物学 氟化酶 含氟模块 生物合成 

分 类 号：Q81[生物学—生物工程]