Novel polyketides synthesized with a higher plant stilbene synthase

The physiological function of the stilbene synthase (STS) from groundnut (Arachis hypogaea) is the formation of resveratrol. The enzyme uses 4-coumaroyl-CoA, performs three condensations with malonyl-CoA, and folds the resulting tetraketide into a new aromatic ring system. We investigated the capacity for building novel and unusual polyketides from alternative substrates. Three types of products were obtained: (a) complete reaction (stilbene-type), (b) three condensations without formation of an aromatic ring (CTAL-type pyrone derailment), and (c) two condensations (BNY-type pyrone derailment). All product types were obtained from 4-fluorocinnamoyl-CoA and analogs in which the coumaroyl moiety was replaced by furan or thiophene. Only type (b) and (c) products were synthesized from other 4-substituted 4-coumaroyl-CoA analogs (-Cl, -Br, -OCH3). Benzoyl-CoA, phenylacetyl-CoA, and medium chain aliphatic CoA esters were poor substrates, and the majority of the products were of type (c). The results show that minor modifications can be used to direct the enzyme reaction to form a variety of different and new products. Manipulation of the biosynthesis of polyketides by synthetic analogs could lead to the development of a chemical library of pharmaceutically interesting novel polyketides.