Engineered route to stilbene biosynthesis in E. coli. Stilbene biosynthesis takes place by sequential addition of acetate units, derived from the decarboxylation of malonyl-CoA, to a CoA activated phenylpropionic acid. Polyketide intermediates (in brackets), if not cyclized properly, can be released from stilbene synthase (STS) and spontaneously form lactone derailment products. Acceptable starter units are extended to a linear tetraketide intermediate, which then undergoes aldol condensation and decarboxylation, followed by aromatization, to produce the proper stilbene structure. E. coli was engineered to produce stilbenes through the biotransformation of phenylpropionic acids by the enzymes 4-coumaroyl:CoA ligase 1 (4CL1) or 4-coumaroyl:CoA ligase 4 (4CL4) and STS. 4-coumaric acid and caffeic acid were transformed to the expected stilbene compounds, resveratrol and piceatannol, using this pathway. Ferulic acid was not converted to the corresponding stilbene using either 4CL1 or 4CL4, but lactone derailment products were detected, indicating that this substrate can be used as a starter unit in vivo.