Journal
METABOLIC ENGINEERING
Volume 35, Issue -, Pages 129-137Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2016.02.012
Keywords
Salinomycin; Genome; Extender unit; Crotonyl-CoA reductase; Polyketide
Categories
Funding
- Ministry of Science and Technology of China [2012AA022107, 2012CB721005, 2012AA02A706]
- National Natural Science Foundation of China [31470157, 31400030]
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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.
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