BioChem - DOS

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

Metabolic engineering

Eichenberger, Michael; Lehka, Beata Joanna; Folly, Christophe; Fischer, David; Martens, Stefan; Simó n, Ernesto; Naesby, Michael

<▼1><P>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 <I>ScTSC13</I> was overexpressed in <I>Saccharomyces cerevisiae</I> to increase its side activity in reducing <I>p</I>-coumaroyl-CoA to <I>p</I>-dihydrocoumaroyl-CoA. <I>De novo</I> 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, <I>de novo</I> production of the antioxidant molecule nothofagin, the antidiabetic molecule phlorizin, the sweet molecule naringin dihydrochalcone, and 3-hydroxyphloretin was achieved.</P></▼1><▼2><P><B>Highlights</B></P><P>&#x2022;<P><I>De novo</I> biosynthesis of phloretin in <I>S. cerevisiae</I>.</P>&#x2022;<P><I>De novo</I> pathway extended to various dihydrochalcones of commercial interest.</P>&#x2022;<P>A barley CHS exhibits very high specificity for phloretin production.</P></P></▼2>

2017

Academic Press

cc-by-nc-nd

1096-7176

1096-7184

39

pp.80-89

10.1016/j.ymben.2016.10.019

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART77197535

CHI, chalcone isomerase; CHS, chalcone synthase; CH3H, chalcone 3-hydroxylase; CPR, cytochrome P450 reductase; CYP, cytochrome P450; C4H, cinnamate 4-hydroxylase; DBR, double bond reductase; DHC, dihydrochalcone; EMA, European Medicine Agency; FDA, Food and Drug Administration; F3H, flavanone 3β-hydroxylase; F3′H, flavonoid 3′-hydroxylase; FLS, flavonol synthase; HRT, homologous recombination tag; NDC, naringin dihydrochalcone; NHDC, neohesperidin dihydrochalcone; OD600, optical density at 600&nbsp; nm; OMT, O-methyltransferase; PAL, phenylalanine ammonia lyase; STS, stilbene synthase; UGT, UDP-dependent-glycosyltransferase; VLC, very long chain; 4CL, 4-coumarate-CoA ligase; Dihydrochalcone; Phlorizin; Nothofagin; Naringin dihydrochalcone; Saccharomyces cerevisiae; Double bond reductase;