Metabolic and pathway engineering to influence native and altered erythromycin production through E. coli |
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| Institution: | 1. State Key Laboratory of Urban and Regional Ecology, Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China;2. School of Chemical and Environmental Engineering, China University of Mining and Technology (Beijing), Beijing 100083, China;3. University of Chinese Academy of Sciences, Beijing 100049, China;1. Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China;2. Graduate University of Chinese Academy of Sciences, Beijing, China;3. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany;4. Department of Pharmaceutical Biotechnology, Saarland University, Building C 2.3, 66123, Saarbrücken, Germany;5. Inner Mongolia New Veyong Biochemical Co., Ltd, Inner Mongolia Dalad Banner, China |
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| Abstract: | The heterologous production of the complex antibiotic erythromycin through Escherichia coli provides a unique challenge in metabolic engineering. In addition to introducing the 19 foreign genes needed for heterologous biosynthesis, E. coli metabolism must be engineered to provide the propionyl-CoA and (2S)-methylmalonyl-CoA substrates required to allow erythromycin formation. In this work, three different pathways to propionyl-CoA were compared in the context of supporting E. coli erythromycin biosynthesis. The comparison revealed that alternative citramalate and threonine metabolic pathways (both starting from exogenous glycerol) were capable of supporting final compound formation equal to a proven pathway reliant upon exogenous propionate. Furthermore, two pathways to (2S)-methylmalonyl-CoA were compared in the production of a novel benzyl-erythromycin analog. A pathway dependent upon exogenous methylmalonate improved selectivity and facilitated antibiotic assessment of this new analog. |
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| Keywords: | Erythromycin Substrate Propionyl-CoA Methylmalonyl-CoA Antibiotic |
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