Terminal Carboxyl Editing Drives Divergence in Fasamycin and Anthrabenzoxocinone Biosynthesis.

Authors

Kai Jiang, Cheng Zhu, Yan Gao, Yuhan Dai, Xiaoli Yan, Lu Yang, Ming Jiang, Zhi Lin, Zixin Deng, Shukun Luo, Xudong Qu

Published in

Journal of the American Chemical Society. Jul 21, 2025. Epub Jul 21, 2025.

Abstract

Aromatic polyketides are a vast category of natural products known for their wide-ranging biological activities, with their structural variety stemming from modifications to their core frameworks. This study reveals two distinct processes that shape the frameworks of (+)/(-)-anthrabenzoxocinone (ABX) and fasamycin (FAS) from a common biosynthetic precursor, compound 1. FasS protects the carboxyl group of this molecule without altering it, preparing it for FasU, which then crafts FAS's unique, nonplanar axial chiral aromatic framework. In contrast, Abx₍₊₎O and Abx_(-)O remove the carboxyl group from compound 1, producing phenyldimethylanthrone (PDA), a key intermediate for (+)/(-)-ABX formation. Structural analysis of AccS (1.65 Å, FasS homologue) and Abx₍₊₎O (1.99 Å), combined with mutagenesis studies, identifies key residues of AccS and Abx₍₊₎O, providing insights into the carboxyl-protecting mechanism and decarboxylation mechanism. Evolutionary and functional studies further connect AccS and AbxO to the N- and C-termini of the long-studied, functionally enigmatic protein family, WhiE-ORFI (resolved in 2.3 Å). This study unveils hidden strategies for terminal carboxyl group editing, providing new insights into the origins of aromatic polyketide diversity.

PMID:
40690660
Bibliographic data and abstract were imported from PubMed on 22 Jul 2025.

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