Deciphering the Biosynthetic Logic for C14 Oxidative Modifications of Polycyclic Tetramate Macrolactams
Peng Jiang , Hongbo Jin , Wenjun Zhang , Wei Tang , Xiaodong Jiang , Yiguang Zhu , Ying Wang , Liping Zhang , Changsheng Zhang
Chinese Journal of Chemistry ›› 2025, Vol. 43 ›› Issue (5) : 483 -490.
Deciphering the Biosynthetic Logic for C14 Oxidative Modifications of Polycyclic Tetramate Macrolactams
Polycyclic Tetramate Macrolactams (PoTeMs) are a family of structurally complex natural products with significant bioactivities. Most of the widespread biosynthetic gene clusters (BGCs) of PoTeMs in bacteria remain silent under normal fermentation conditions. Herein, we report the construction of an efficient chassis (306A) to facilitate the heterologous studies of PoTeM BGCs, which reveals a biosynthetic logic for sequential C14 modifications of PoTeMs through characterizing a PoTeM gene cluster ( fla) from marine-derived Streptomyces falvogriseus SCSIO 40032. The C14 hydroxylation was mediated by flavin-dependent oxidoreductase FlaB1 when catalyzing the crucial C6—C13 cyclization, which was supported by feeding and 18O 2 labeling studies; the C14-OH groups in 5/5/6-type PoTeMs are subsequently converted to ketones by the cytochrome P450 enzyme FlaD. The FlaD homologs FtdF and SSHG_05717 were assayed to show similar functions as FlaD. Besides, the crystal structure of pactamide N ( 5) provides a critical reference for determining the absolute configuration of 5/5/6-type PoTeMs lacking C14 modifications. This study not only affords an efficient chassis for studying silent PoTeM BGCs, but also provides insights into the biosynthetic logic for C14 oxidative modifications of predominant 5/5- and 5/5/6-type PoTeMs.
PoTeMs / Chassis cell / Biosynthesis / Cytochrome P450 enzyme / C—C coupling / Oxidoreductases
2024 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
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