Enhanced salinomycin production by adjusting the supply of polyketide extender units in Streptomyces albus
Enhanced salinomycin production by adjusting the supply of polyketide extender units in Streptomyces albus
复制标题
通过调整白色链霉菌中聚酮化合物增量剂单元的供应来提高盐霉素产量
DOI：
10.1016/j.ymben.2016.02.012
复制
发表时间：
2016-05-01
影响因子：
8.4
通讯作者：
Bai, Linquan
中科院分区：
文献类型：
--
作者：
Lu, Chenyang;Zhang, Xiaojie;Bai, Linquan
抗球虫盐霉素是由白色链霉菌产生的聚酮化合物，并且需要丙二酰-CoA、甲基丙二酰-CoA和乙基丙二酰-CoA用于主链组装。S. albus DSM 41398揭示了高百分比的参与脂质代谢的基因，支持了在富含油的培养基中的高盐霉素产量。基因组中的7个PKS/PKS-NRPS基因簇被发现是活跃转录的，并已被单独删除，这导致显着提高盐霉素生产。然而，PKS-NRPS-2和PKS-6的组合缺失没有显示进一步的改善。而丙二酰-CoA和甲基丙二酰-CoA的浓度增加，乙基丙二酰-CoA的浓度在突变体中保持较低。在APKS-NRPS-2/APKS-6突变体中过表达内源性巴豆酰辅酶A还原酶基因（ccr），从而提高产量。簇缺失和ccr基因过表达的组合导致盐霉素的总体滴度从0.60提高到6.60 g/L。该工程策略可用于各种天然聚酮化合物的生产。(C)2016国际代谢工程学会。爱思唯尔公司出版All rights reserved.
The anticoccidial salinomycin is a polyketide produced by Streptomyces albus and requires malonyl-CoAs, methylmalonyl-CoAs, and ethylmalonyl-CoAs for the backbone assembly. Genome sequencing of S. albus DSM 41398 revealed a high percentage of genes involved in lipid metabolism, supporting the high salinomycin yield in oil-rich media. Seven PKS/PKS-NRPS gene clusters in the genome were found to be actively transcribed and had been individually deleted, which resulted in significantly improved salinomycin production. However, a combined deletion of PKS-NRPS-2 and PKS-6 showed no further improvement. Whereas the concentrations of malonyl-CoA and methylmalonyl-CoA were increased, the concentration of ethylmalonyl-CoA remained low in the mutants. An endogenous crotonyl-CoA reductase gene (ccr) was overexpressed in the APKS-NRPS-2/APKS-6 mutant, resulting in improved production. Combination of cluster deletions and over-expression of ccr gene led to an overall titer improvement of salinomycin from 0.60 to 6.60 g/L. This engineering strategy can be implemented for various natural polyketides production. (C) 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.