Combinatorial biosynthesis of plant medicinal polyketides by microorganisms

Combinatorial biosynthesis includes an approach in which genes from different organisms are assembled to design and construct an artificial gene cluster for production of bioactive compounds. An Escherichia coli system carrying artificial biosynthetic pathways for production of plant-specific medicinal polyketides, such as flavonoids, stilbenoids, isoflavonoids, and curcuminoids, was designed and expressed. Starting with amino acids tyrosine and phenylalanine as substrates, this system yielded, for example, naringenin, resveratrol, genistein, and curcumin. Supplementation of unnatural carboxylic acids as precursors to the E. coli cells led to production of unnatural compounds. Addition of modification enzymes to the artificial pathways led to production of natural and unnatural flavonols, flavones, and methylated resveratrols. This microbial system is promising not only for construction of larger libraries by employing other polyketide synthases and modification enzymes of various origins as members of the artificial pathway but also for efficient use of the potential of the host microorganisms.