An unusual aromatase/cyclase programs the formation of the phenyldimethylanthrone framework in anthrabenzoxocinones and fasamycin

• 成果类型: Article
• 署名作者: Jiang, Kai; Chen, Xu; Yan, Xiaoli; Li, Guangjun; Lin, Zhi; Deng, Zixin; Luo, Shukun; Qu, Xudong
• 署名单位: Shanghai Jiao Tong University; Wuhan University; Shanghai Jiao Tong University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8881
• DOI: 10.1073/pnas.2321722121
• 发表日期: 2024-03-12
• 关键词: ii polyketide synthases; streptomyces sp; functional-analysis; chemical diversity; biosynthesis; naphthacemycins; antibiotics; cyclization; coelicolor; benastatin

摘要

Aromatic polyketides are renowned for their wide- ranging pharmaceutical activities. Their structural diversity is mainly produced via modification of limited types of basic frameworks. In this study, we characterized the biosynthesis of a unique basic aromatic framework, phenyldimethylanthrone (PDA) found in (+)/(-)- anthrabenzoxocinones (ABXs) and fasamycin (FAS). Its biosynthesis employs a methyltransferase (Abx(+)M/ Abx(-)M/FasT) and an unusual TcmI-like aromatase/cyclase (ARO/CYC, Abx(+)D/ Abx(-)D/FasL) as well as a nonessential helper ARO/CYC (Abx(+)C/Abx(-)C/FasD) to catalyze the aromatization/cyclization of polyketide chain, leading to the formation of all four aromatic rings of the PDA framework, including the C9 to C14 ring and a rare angular benzene ring. Biochemical and structural analysis ofAbx(+)D reveals a unique loop region, giving rise to its distinct acyl carrier protein- dependent specificity compared to other conventional TcmI-type ARO/CYCs, all of which impose on free molecules. Mutagenic analysis discloses critical residues of Abx(+)D for its catalytic activity and indicates that the size and shape of its interior pocket determine the orientation of aromatization/cyclization. This study unveils the tetracyclic and non-TcmN type C9 to C14 ARO/CYC, significantly expanding our cognition of ARO/CYCs and the biosynthesis of aromatic polyketide framework.