<jats:title>Abstract</jats:title><jats:p>The biosynthesis of aromatic polyketides derived from type II polyketide synthases (PKSs) is complex, and it is not uncommon that highly similar gene clusters give rise to diverse structural architectures. The<jats:italic>act</jats:italic>biosynthetic gene cluster (BGC) of the model actinomycete<jats:italic>Streptomyces coelicolor</jats:italic> A3(2) is an archetypal type II PKS. Here we show that the<jats:italic>act</jats:italic>BGC also specifies the aromatic polyketide GTRI‐02 (<jats:bold>1</jats:bold>) and propose a mechanism for the biogenesis of its 3,4‐dihydronaphthalen‐1(2<jats:italic>H</jats:italic>)‐one backbone. Polyketide <jats:bold>1</jats:bold>was also produced by<jats:italic>Streptomyces</jats:italic>sp. MBT76 after activation of the<jats:italic>act</jats:italic>‐like<jats:italic>qin</jats:italic>gene cluster by overexpression of the pathway‐specific activator. Mining of this strain also identified dehydroxy‐GTRI‐02 (<jats:bold>2</jats:bold>), which most likely originated from dehydration of<jats:bold>1</jats:bold>during the isolation process. This work shows that even extensively studied model gene clusters such as<jats:italic>act</jats:italic>of<jats:italic>S. coelicolor</jats:italic>can still produce new chemistry, offering new perspectives for drug discovery.