Metabolic engineering of Saccharomyces cerevisiae for de novo production of dihydrochalcones with known antioxidant, antidiabetic, and sweet tasting properties

• Published in: Metabolic engineering 2017-01, Vol.39, p.80-89
• Main Authors: Eichenberger, Michael, Lehka, Beata Joanna, Folly, Christophe, Fischer, David, Martens, Stefan, Simón, Ernesto, Naesby, Michael
• Format: Article
• Language: English
• Subjects: Antioxidants - administration & dosage; Biosynthetic Pathways - physiology; Chalcones - administration & dosage; Chalcones - biosynthesis; Dihydrochalcone; Double bond reductase; Genetic Enhancement - methods; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - metabolism; Metabolic Engineering - methods; Metabolic Networks and Pathways - physiology; Naringin dihydrochalcone; Nothofagin; Original; Phlorizin; Saccharomyces cerevisiae; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - metabolism; Sweetening Agents - administration & dosage; Sweetening Agents - metabolism
• ISSN: 1096-7176; 1096-7184
• DOI: 10.1016/j.ymben.2016.10.019

Dihydrochalcones are plant secondary metabolites comprising molecules of significant commercial interest as antioxidants, antidiabetics, or sweeteners. To date, their heterologous biosynthesis in microorganisms has been achieved only by precursor feeding or as minor by-products in strains engineered for flavonoid production. Here, the native ScTSC13 was overexpressed in Saccharomyces cerevisiae to increase its side activity in reducing p-coumaroyl-CoA to p-dihydrocoumaroyl-CoA. De novo production of phloretin, the first committed dihydrochalcone, was achieved by co-expression of additional relevant pathway enzymes. Naringenin, a major by-product of the initial pathway, was practically eliminated by using a chalcone synthase from barley with unexpected substrate specificity. By further extension of the pathway from phloretin with decorating enzymes with known specificities for dihydrochalcones, and by exploiting substrate flexibility of enzymes involved in flavonoid biosynthesis, de novo production of the antioxidant molecule nothofagin, the antidiabetic molecule phlorizin, the sweet molecule naringin dihydrochalcone, and 3-hydroxyphloretin was achieved. •De novo biosynthesis of phloretin in S. cerevisiae.•De novo pathway extended to various dihydrochalcones of commercial interest.•A barley CHS exhibits very high specificity for phloretin production.