De Novo Production of Piceatannol via Construction of Interconnected Biosynthetic Pathways in a Single Saccharomyces cerevisiae Strain

Piceatannol, a stilbene widely found in many types of foods, shows a variety of effects on the cardiovascular system, nervous system, and skin. Its low abundance in nature impedes its development. Microbial cell factories offer a green and sustainable approach to the production of natural products. In this study, we screened two 4-coumarate:coenzyme A ligases (4CLs), nine stilbene synthases (STSs), and five 4-hydroxyphenylacetate-3-hydroxylases (4HPA3Hs) to construct multiple bioconversion routes from p-coumaric acid to piceatannol in a single Saccharomyces cerevisiae strain. Then, the supply of p-coumaric acid and malonyl-CoA was enhanced, and NADPH and FADH₂ regenerations were optimized, resulting in establishment of yPi101 which produced 127 mg/L and 442 mg/L piceatannol in a flask and by fed-batch fermentation, respectively. This is the first report of the de novo production of piceatannol in a single S. cerevisiae strain and represents the highest piceatannol yield.