<br>丝状真菌中细胞孢子酮的生物合成,Journal of the American Chemical Society

当前位置： X-MOL 学术 › J. Am. Chem. Soc. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

丝状真菌中细胞孢子酮的生物合成
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-02-22 , DOI: 10.1021/jacs.3c14066
Li Li _{1,

2} , Weimao Zhong ₁ , Hang Liu _{1,

3} , Patricia Espinosa-Artiles ₁ , Ya-Ming Xu ₁ , Chen Wang _{1,

3} , Jose Manuel Verdugo Robles ₁ , Tiago Antunes Paz ₄ , Marielle Cascaes Inácio ₁ , Fusheng Chen _{5,

6} , Yuquan Xu ₃ , A A Leslie Gunatilaka ₁ , István Molnár _{1,

7}

Affiliation

具有异色满-3-酮药效基团的聚酮化合物在真菌天然产物中很少见，因为它们的生物合成需要非正统的 S 型芳环环化。基因组挖掘在选定的leotiomycetous真菌中发现了一个保守的基因簇，该基因簇编码细胞孢子酮的生物合成，包括isochroman-3-one同源物。酿酒酵母中全生物合成和生物催化形式的组合生物合成以及使用纯化酶的关键反应的体外重建揭示了细胞孢子酮结构和生物活性多样性是如何产生的。细胞孢子酮的 S 型酰基二羟基苯乙酸 (ADA) 核心由协作的聚酮合酶对组装。硫酯酶结构域催化的酯交换反应释放 ADA 酯，其中一些是已知的 Nur77 调节剂。或者，水解释放允许 C6 通过黄素依赖性单加氧酶羟基化，产生三羟基苯部分。通过短链脱氢酶/还原酶还原 C9 羰基会引发 isochroman-3-one 形成，从而提供具有细胞毒性和抗菌活性的细胞孢子酮。烯酰二-或三羟基苯乙酸作为分流产物生成，而异可尔曼-3,4-二酮通过自氧化形成。细胞孢子途径为组合合成生物学提供了新型聚酮化合物生物合成酶，以促进用于药物发现的“非天然”天然产物的生产。

"点击查看英文标题和摘要"

Biosynthesis of Cytosporones in Leotiomycetous Filamentous Fungi

Polyketides with the isochroman-3-one pharmacophore are rare among fungal natural products as their biosynthesis requires an unorthodox S-type aromatic ring cyclization. Genome mining uncovered a conserved gene cluster in select leotiomycetous fungi that encodes the biosynthesis of cytosporones, including isochroman-3-one congeners. Combinatorial biosynthesis in total biosynthetic and biocatalytic formats in Saccharomyces cerevisiae and in vitro reconstitution of key reactions with purified enzymes revealed how cytosporone structural and bioactivity diversity is generated. The S-type acyl dihydroxyphenylacetic acid (ADA) core of cytosporones is assembled by a collaborating polyketide synthase pair. Thioesterase domain-catalyzed transesterification releases ADA esters, some of which are known Nur77 modulators. Alternatively, hydrolytic release allows C6 hydroxylation by a flavin-dependent monooxygenase, yielding a trihydroxybenzene moiety. Reduction of the C9 carbonyl by a short chain dehydrogenase/reductase initiates isochroman-3-one formation, affording cytosporones with cytotoxic and antimicrobial activity. Enoyl di- or trihydroxyphenylacetic acids are generated as shunt products, while isocroman-3,4-diones are formed by autoxidation. The cytosporone pathway offers novel polyketide biosynthetic enzymes for combinatorial synthetic biology to advance the production of “unnatural” natural products for drug discovery.

更新日期：2024-02-22

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南