title: Enhanced salinomycin production by adjusting the supply of polyketide extender units in Streptomyces albus.
abstract: 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 ΔPKS-NRPS-2/ΔPKS-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 6.60g/L. This engineering strategy can be implemented for various natural polyketides production.
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China; Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Chenyang
authors.initials: C
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China; Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China; Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China; Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: bailq@sjtu.edu.cn.
authors.forename: Linquan
authors.initials: L
authors.lastname: Bai
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D044944:Acyl-CoA Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D060847:Metabolic Engineering; D048630:Polyketide Synthases / Q000096:biosynthesis / Q000235:genetics; D061065:Polyketides / Q000378:metabolism*; D011714:Pyrans / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000214:Acyl Coenzyme A; D044944:Acyl-CoA Dehydrogenases; D001426:Bacterial Proteins; D048630:Polyketide Synthases; D061065:Polyketides; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides; C100154:acyl-CoA dehydrogenase (NADP+)
keywords: Crotonyl-CoA reductase; Extender unit; Genome; Polyketide; Salinomycin