The avermectin initial aglycon is synthesized by the polyketide synthase activity of four proteins (AVES 1, AVES 2, AVES 3, and AVES 4). The activity of this enzyme complex is similar to type I polyketide synthases. Either 2-methylbutyrl CoA or isobutyrl CoA can be used as starting units and are extended by seven acetate units and five propionate units to produce avermectin “a” series or “b” series, respectively. The initial aglycon is subsequently released from the thioesterase domain of AVES 4 by formation of an intramolecular cyclic ester.