Fogacin and two novel fogacin derivatives, fogacins B and C, were isolated from the rare actinomycete Actinoplanes missouriensis. Biosynthesis of fogacin C apparently requires β alkylation of a polyketide chain. The fogacin biosynthetic type II polyketide synthase (PKS) gene cluster contains a hydroxymethylglutaryl‐coenzyme A synthase (HCS) cassette, which is usually responsible for β alkylation in the type I PKS system. Another characteristic of the fog cluster is that it encodes two sets of ketosynthase (KS) and chain‐length factor (CLF). Inactivation of either of the two KS genes in A. missouriensis and heterologous expression of the HCS cassette with either of the two KS‐CLF genes in Streptomyces albus indicated that each KS‐CLF had a different starter substrate specificity: one preferred an unusual β‐alkylated starter and the other preferred a normal acetyl starter. This study expands knowledge of HCS cassette‐dependent β alkylation into the type II PKS system and provides a natural example of combinatorial biosynthesis for producing diverse polyketides from different starter substrates.

The cover feature picture shows a unique polyketide biosynthesis pathway in Actinoplanes missouriensis. β‐Alkylation machinery encoded by an HCS cassette and two sets of KS‐CLF with different starter substrate specificities enhances the structural diversity of its final products. The background shows A. missouriensis sporangia formed on substrate mycelium. More information can be found in the full paper by Y. Katsuyama, Y. Ohnishi, et al. on page 1039 in Issue 8, 2019 (DOI: 10.1002/cbic.201800640).