南京大学谭仁祥团队报道了Skyrin和RugulosinA的交织生物合成是笼状双蒽醌形成的基础。相关研究成果于2021年8月25日发表在国际顶尖学术期刊《美国化学会杂志》。

Skyrin和rugulosin A是在许多真菌中发现的具有生物活性的双蒽醌类化合物，前者被认为是金丝桃素（一种具有多种生物活性的植物化学物质）的前体，而后者具有独特的笼状结构。然而，尽管他们已经被描述了60多年，但其生物合成途径仍然是神秘的。

该文中，研究人员提出了rug基因簇，该基因簇同时控制Talaromyces sp.YE3016中skyrin和rugulosin A的生物合成，Talaromyces sp.YE3016是一种居住在乌头属carmichaeli中的真菌内生菌。基因组测序、基因失活、异源表达和生物转化试验相结合，可以识别基因功能、生物合成前体和参与其分子结构构建的酶组。

特别是，skyrin被证明是由RugG催化的大黄素自由基5,5′-二聚形成的，RugG是一种细胞色素P450单加氧酶，被证明可能适用于二聚多酚的（化学）酶合成。真菌醛酮还原酶RugH被证明能够在大黄素自由基偶联后立即劫持最近的skyrin前体（CSP），催化CSP的酮还原以使其互变异构失活为skyrin，从而能够自发的分子内Michael加成将酮还原形式的CSP环化为rugulosin A，其是多种笼状结构双蒽醌的代表。

总的来说，该工作更新了人们对双蒽醌生物合成的理解，并为合成生物学研究skyrin、rugulosin A及其同类化合物铺平了道路。

附：英文原文

Title: Intertwined Biosynthesis of Skyrin and Rugulosin A Underlies the Formation of Cage-Structured Bisanthraquinones

Author: Yun Bin Han, Wei Bai, Chun Xia Ding, Jie Liang, Shao-Hua Wu, Ren Xiang Tan

Issue&Volume: August 25, 2021

Abstract: Skyrin and rugulosin A are bioactive bisanthraquinones found in many fungi, with the former suggested as a precursor of hypericin (a diversely bioactive phytochemical) and the latter characterized by its distinct cage-like structure. However, their biosynthetic pathways remain mysterious, although they have been characterized for over six decades. Here, we present the rug gene cluster that governs simultaneously the biosynthesis of skyrin and rugulosin A in Talaromyces sp. YE3016, a fungal endophyte residing in Aconitum carmichaeli. A combination of genome sequencing, gene inactivation, heterologous expression, and biotransformation tests allowed the identification of the gene function, biosynthetic precursor, and enzymatic sets involved in their molecular architecture constructions. In particular, skyrin was demonstrated to form from the 5,5′-dimerization of emodin radicals catalyzed by RugG, a cytochrome P450 monooxygenase evidenced to be potentially applicable for the (chemo)enzymatic synthesis of dimeric polyphenols. The fungal aldo-keto reductase RugH was shown to be capable of hijacking the closest skyrin precursor (CSP) immediately after the emodin radical coupling, catalyzing the ketone reduction of CSP to inactivate its tautomerization into skyrin and thus allowing for the spontaneous intramolecular Michael addition to cyclize the ketone-reduced form of CSP into rugulosin A, a representative of diverse cage-structured bisanthraquinones. Collectively, the work updates our understanding of bisanthraquinone biosynthesis and paves the way for synthetic biology accesses to skyrin, rugulosin A, and their siblings.

DOI: 10.1021/jacs.1c05421

Source: https://pubs.acs.org/doi/10.1021/jacs.1c05421