A heterologous expression platform in Aspergillus nidulans for the elucidation of cryptic secondary metabolism biosynthetic gene clusters: discovery of the Aspergillus fumigatus sartorypyrone biosynthetic pathway.
A heterologous expression platform in Aspergillus nidulans for the elucidation of cryptic secondary metabolism biosynthetic gene clusters: discovery of the Aspergillus fumigatus sartorypyrone biosynthetic pathway.
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DOI：
10.1039/d3sc02226a
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发表时间：
2023-10-18
期刊：
影响因子：
8.4
通讯作者：
Oakley, Berl R.
中科院分区：
文献类型：
--
作者：
Lin, Shu-Yi;Oakley, C. Elizabeth;Jenkinson, Cory B.;Chiang, Yi-Ming;Lee, Ching-Kuo;Jones, Christopher G.;Seidler, Paul M.;Nelson, Hosea M.;Todd, Richard B.;Wang, Clay C. C.;Oakley, Berl R.
烟曲霉是一种严重的人类病原体，可导致免疫功能低下患者发生危及生命的曲霉病。次级代谢产物在疾病的发病机制中起着重要作用，但许多次级代谢产物的生物合成基因簇（BGC）仍不清楚。在这项研究中，我们已经开发了一个异源表达平台，在构巢曲霉，使用一个新创建的基因去复制菌株，表达一个以前未知的BGC从A。并测定其产物。BGC生产sartorypyrones，我们将其命名为间谍BGC。通过HRESIMS、NMR和微晶电子衍射（MicroED）对靶基因缺失的分析使我们能够从间谍BGC中鉴定出12种产物。其中7种化合物以前未被分离。我们还单独表达了聚酮合酶（PKS）基因spyA，并证明它产生聚酮三乙酸内酯（TAL），一种潜在的重要的生物可再生平台化学品。我们的数据使我们能够提出sartorypyrones和相关天然产物的生物合成途径。这项工作突出了使用A. nidulans异源表达平台以揭示来自A.烟曲霉和其他物种，尽管其次级代谢组的复杂性。次生代谢产物在真菌烟曲霉的致病过程中起着重要作用，烟曲霉可引起致死性曲霉病。表达A.真菌构巢曲霉中的烟曲霉基因揭示了新的A.烟曲霉次生代谢产物
Aspergillus fumigatus is a serious human pathogen causing life-threatening Aspergillosis in immunocompromised patients. Secondary metabolites (SMs) play an important role in pathogenesis, but the products of many SM biosynthetic gene clusters (BGCs) remain unknown. In this study, we have developed a heterologous expression platform in Aspergillus nidulans, using a newly created genetic dereplication strain, to express a previously unknown BGC from A. fumigatus and determine its products. The BGC produces sartorypyrones, and we have named it the spy BGC. Analysis of targeted gene deletions by HRESIMS, NMR, and microcrystal electron diffraction (MicroED) enabled us to identify 12 products from the spy BGC. Seven of the compounds have not been isolated previously. We also individually expressed the polyketide synthase (PKS) gene spyA and demonstrated that it produces the polyketide triacetic acid lactone (TAL), a potentially important biorenewable platform chemical. Our data have allowed us to propose a biosynthetic pathway for sartorypyrones and related natural products. This work highlights the potential of using the A. nidulans heterologous expression platform to uncover cryptic BGCs from A. fumigatus and other species, despite the complexity of their secondary metabolomes. Secondary metabolites are important for the pathogenesis of the fungus Aspergillus fumigatus which causes lethal Aspergillosis. Expressing groups of A. fumigatus genes in the fungus Aspergillus nidulans reveals new A. fumigatus secondary metabolites.
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影响因子：
7.8
作者：
Chiang, Yi-Ming;Chang, Shu-Lin;Oakley, Berl R.;Wang, Clay C. C.
通讯作者：
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影响因子：
14.8
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影响因子：
2.1
作者：
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通讯作者：
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影响因子：
4
作者：
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通讯作者：
Oakley, Berl R.
影响因子：
15
作者：
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通讯作者：
Oakley, Bed R.