title: Metabolic and pathway engineering to influence native and altered erythromycin production through E. coli.
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.
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Chemical and Biological Engineering, The State University of New York at Buffalo, Buffalo, NY 14260, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Blaine A
authors.initials: BA
authors.lastname: Pfeifer
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D004917:Erythromycin / Q000031:analogs & derivatives / Q000096:biosynthesis*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism*; D060847:Metabolic Engineering
chemical_list: D000214:Acyl Coenzyme A; C015357:methylmalonyl-coenzyme A; C009061:propionyl-coenzyme A; D004917:Erythromycin; D005990:Glycerol
keywords: Antibiotic; E. coli; Erythromycin; Methylmalonyl-CoA; Propionyl-CoA; Substrate