美国宾夕法尼亚大学教授Xue Gao及其团队提出了含硫环五色酮的酶环收缩生物合成。该项研究成果发表在2024年12月16日出版的《美国化学会杂志》上。

据悉，环五色酮，以其6/6/5杂三环结构而闻名，是许多生物活性天然产物的关键组成部分，但其酶的起源尚不清楚。

研究小组发现了一类新的含环五色酮的化合物，称为异色亚砜，其特征是独特的C-S键。团队还发现了一种独特的FAD依赖单加氧酶IscL，该酶催化6/6/6的呫吨酮中间体通过苯环收缩生成6/6/5环戊二烯中间体, 2S-remisporine A。2S-remisporine A的高反应活性进一步促进了与含巯基化合物的自发巯基-Micheal加成反应，在异色亚砜中形成C-S键。

此外，研究人员证明了IscL同源物介导了呫吨酮中间体苯环修饰的分叉途径，导致环收缩或裂解，这是由230位的关键残基苯丙氨酸或酪氨酸决定的。他们的发现强调了IscL在形成6/6/5环五色酮支架中的关键作用，并为其催化机制提供了深入的见解。他们的工作为含环五色酮化合物的基因组挖掘打下了基础，并显示了IscL在生物催化方面的潜在应用。

附：英文原文

Title: Enzymatic Ring Contraction for the Biosynthesis of Sulfur-Containing Cyclopentachromone

Author: Qiuyue Nie, Chunxiao Sun, Shuai Liu, Qiang Li, Maria Zotova, Tong Zhu, Xue Gao

Issue&Volume: December 16, 2024

Abstract: Cyclopentachromone, distinguished by its 6/6/5 heterotricyclic ring structure, is a key building block in many bioactive natural products, yet its enzymatic origin remains unclear. We identified a new class of cyclopentachromone-containing compounds, termed isochromosulfines, characterized by unique C–S bonds. A distinct FAD-dependent monooxygenase, IscL, was identified to catalyze the formation of the 6/6/5 cyclopentadiene intermediate, 2S-remisporine A, from a 6/6/6 xanthone precursor via benzene ring contraction. The high reactivity of 2S-remisporine A further promotes a spontaneous thiol-Micheal addition reaction with thiol-containing compounds, forming the C–S bond in isochromosulfines. Additionally, we demonstrate that IscL homologues mediate a bifurcated pathway of benzene ring modification in the xanthone intermediate, leading to either ring contraction or cleavage, which is determined by a critical residue at position 230 to be phenylalanine or tyrosine. Our findings highlight the pivotal role of IscL in forming the 6/6/5 cyclopentachromone scaffold and offer deep insights into its catalytic mechanism. Our work lays the foundation for genome mining of cyclopentachromone-containing compounds and shows the potential application of IscL in biocatalysis.

DOI: 10.1021/jacs.4c11906

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c11906