阿维菌素产生菌的生物技术改造研究进展

Research progresses on engineering Streptomyces avermectiniusthrough biotechnology

目的综述近年来运用基因工程技术对阿维菌素产生菌改良的研究进展。方法在查阅国内外文献近100篇的基础上,介绍了阿维菌素的生物合成途径,产生多组分的3个关键酶及阿维菌素产生菌改良的研究进展,包括选择性生产有效组分,产生新抗生素、杂合抗生素,改进生产工艺以及提高菌种产抗生素量。结果目前国内外均已经构建了只产生B组分及寡霉素基因缺失或失活的工程菌。分别运用突变结合理性化筛选和特定基因重组提高活性高的组分的产量,并且通过基因改造产生多种阿维菌素的衍生物;将透明颤菌的血红蛋白基因引入阿维菌素产生菌,改进氧的供应,阿维菌素的产量不断提高。阿维菌素生物合成调控机制和组合生物学改造聚酮合成酶等方面仍需深入研究。结论利用生物技术改造阿维菌素产生菌在组分改造、结构修饰、产品收率、生产工艺改进等方面已取得显著进展。对阿维菌素和其他聚酮体药物产生菌的生物合成、基因改造起着重要作用,使生产简化,成本降低,药物应用更广泛。

Objective To describe the current research progresses achieved in engineering Streptomyces averrnectinius through mutagenesis and recombinant DNA technology. Methods Based on the elucidation of the biochemistry and genetics of avermectin biosynthesis, as well as the complete determination of avermectin biosynthesis gene cluster and the entire genome of Streptomyces avermectinius, the paper deals with engineering Streptornyces avermectinius through biotechnology. These progresses include selective production of desired components by pathway engineering, enhancement of the yield of avermectin especially through cloning manipulating regulatory genes instead of the traditional methods, such as random mutagenesis, production of novel avermectin via mutational biosynthesis and the improvement of avermectin ferment. Results The selective production of avermectin has achieved excellent progress up to now. The mutational strains can produce only components B of avermectins, that oligomycin biosynthesis gene cluster and aveD gene has been deleted. Combinational biosythesis has been proved to be a new approach to generate novel avermectins derivatives. However, there is still a need for revealing the complex regulatory mechanism and so on. Conclusions The availability of Streptomyces avermectinius genome and accumulation of the complicated regulatory mechanism information in combination with the recent development of combinatorial biosynthesis should us to engineer Streptomyces avermectinius as a more efficient host for the production of important commercial drugs.