9/18（金）16:00-17:30 第220回創薬科学セミナー「Complete fermentative biosynthesis of doxorubicin and its derivatives in engineered Escherichia coli」

Doxorubicin is a frontline anthracycline anticancer drug listed on the WHO Model List of Essential Medicines, yet its supply depends on fermentation of Streptomyces peucetius followed by multistep semisynthesis—a route constrained by the limited engineering toolkit and complex regulation of the native producer, and by low overall yields. Here we report the complete biosynthesis of doxorubicin and its derivatives in engineered Escherichia coli. A type II minimal polyketide synthase was first optimized for decaketide formation using resistomycin as a surrogate reporter, and DpsC was identified as a fidelity factor favoring propionyl-CoA as the starter unit. Combined with enhanced malonyl-CoA supply and chaperone engineering, this enabled production of ε-rhodomycinone and doxorubicinone. We separately reconstructed biosynthesis of the noncanonical sugar TDP-L-daunosamine and DnrQS-mediated glycosylation. To relieve metabolic burden, a strain harboring the core aglycone biosynthesis genes was cocultured with a second strain harboring the sugar biosynthesis and glycosylation genes, enabling complete biosynthesis of doxorubicin from glucose and propionate in fed-batch fermentation. Further introduction of an epimerase or an O-methyltransferase yielded epirubicin and non-natural 4′-O-methyl-doxorubicin, respectively, establishing E. coli as a modular platform for the fermentative production of medicinally important aromatic polyketides.