Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis.
Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis.
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DOI：
10.1021/jacs.3c02011
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发表时间：
2023-05
影响因子：
15
通讯作者：
Run Yang;Jian Feng;Hao Xiang;Bin Cheng;Li-Dong Shao;Yan-ping Li;Hang Wang;Qiu-Fen Hu;Weilie Xiao;Yudai Matsuda;Wei-Guang Wang
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文献类型：
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作者：
Run Yang;Jian Feng;Hao Xiang;Bin Cheng;Li-Dong Shao;Yan-ping Li;Hang Wang;Qiu-Fen Hu;Weilie Xiao;Yudai Matsuda;Wei-Guang Wang
烷基水杨醛衍生物是一类广泛存在于真菌中的聚酮类天然产物，具有结构多样性。它们的生物合成机制最近得到了深入的研究，然而，参与真菌烷基水杨醛生物合成的聚酮酶（PKS）如何释放其产物仍然是难以捉摸的。在这项研究中，我们发现了一个孤儿的水杨醛衍生物的生物合成基因簇的真菌Stachybocyansp.g12。有趣的是，由基因簇编码的高度还原性PKS StrA执行还原性聚酮化合物链释放，尽管它缺乏C-末端还原酶结构域，这通常是这种还原性释放所需的。我们的研究表明，链的释放是通过StrA的酮还原酶（KR）结构域实现的，该结构域在聚酮链延伸过程中也进行典型的β-酮还原。此外，我们发现，cupin结构域的蛋白质StrC在芳构化反应中起着至关重要的作用。总的来说，我们提供了一个前所未有的KR结构域催化的聚酮链释放的例子，以及水杨醛支架如何在真菌中产生的更清晰的图像。
Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical β-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi.