Identification and Analysis of the Biosynthetic Gene Cluster for the Indolizidine Alkaloid Iminimycin in Streptomyces griseus

• Published in: Chembiochem : a European journal of chemical biology 2022-02, Vol.23 (3), p.e202100517-n/a
• Main Authors: Tsutsumi, Hayama, Katsuyama, Yohei, Tezuka, Takeaki, Miyano, Rei, Inahashi, Yuki, Takahashi, Yoko, Nakashima, Takuji, Ohnishi, Yasuo
• Format: Article
• Language: English
• Subjects: Acyltransferase; Alkaloids; Alkaloids - biosynthesis; Alkaloids - chemistry; Biosynthesis; Genes; iminium; Inactivation; indolizidines; Indolizidines - chemistry; Modules; Molecular Conformation; Multigene Family; polyketides; Streptomyces; Streptomyces griseus; Streptomyces griseus - chemistry; Streptomyces griseus - genetics; Streptomyces griseus - metabolism
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202100517

Indolizidine alkaloids, which have versatile bioactivities, are produced by various organisms. Although the biosynthesis of some indolizidine alkaloids has been studied, the enzymatic machinery for their biosynthesis in Streptomyces remains elusive. Here, we report the identification and analysis of the biosynthetic gene cluster for iminimycin, an indolizidine alkaloid with a 6‐5‐3 tricyclic system containing an iminium cation from Streptomyces griseus. The gene cluster has 22 genes, including four genes encoding polyketide synthases (PKSs), which consist of eight modules in total. In vitro analysis of the first module revealed that its acyltransferase domain selects malonyl‐CoA, although predicted to select methylmalonyl‐CoA. Inactivation of seven tailoring enzyme‐encoding genes and structural elucidation of four compounds accumulated in mutants provided important insights into iminimycin biosynthesis, although some of these compounds appeared to be shunt products. This study expands our knowledge of the biosynthetic machinery of indolizidine alkaloids and the enzymatic chemistry of PKS. The biosynthetic gene cluster for iminimycin, an indolizidine alkaloid with a 6‐5‐3 tricyclic system containing an iminium cation from Streptomyces griseus, was identified. It has 22 genes, including four genes encoding polyketide synthases, which consist of eight modules. Inactivation of seven tailoring enzyme‐encoding genes and structural elucidation of compounds accumulated in the mutants provided important insights into iminimycin biosynthesis.