Engineering precursor flow for increased erythromycin production in Aeromicrobium erythreum.
Metabolic engineering technology for industrial microorganisms is under development to create rational, more reliable, and more cost-effective approaches to strain improvement. Strain improvement is a critical component of the drug development process, yet the genetic basis for high production by industrial microorganisms is still a mystery. In this study, a search was begun for genetic modifications critical for high-level antibiotic production. The model system used was erythromycin production studied in the unicellular actinomycete, Aeromicrobium erythreum. A tagged-mutagenesis approach allowed reverse engineering of improved strains, revealing two genes, mutB and cobA, in the primary metabolic branch for methylmalonyl-CoA utilization. Knockouts in these genes created a permanent metabolic switch in the flow of methylmalonyl-CoA, from the primary branch into a secondary metabolic branch, driving erythromycin overproduction. The model provides insights into the regulation and evolution of secondary metabolism.
Reeves
Andrew R
AR
Fermalogic, Inc., 2201 West Campbell Park Drive, Chicago, IL 60612, USA.
Cernota
William H
WH
Brikun
Igor A
IA
Wesley
Roy K
RK
Weber
J Mark
JM
D039903:Actinobacteria / Q000235:genetics / Q000502:physiology*; D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004917:Erythromycin / Q000096:biosynthesis*; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics* / Q000502:physiology; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*
D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; C015357:methylmalonyl-coenzyme A; D004917:Erythromycin; D008780:Methyltransferases; C060508:uroporphyrin-III C-methyltransferase