Arimetamycin A: improving clinically relevant families of natural products through sequence-guided screening of soil metagenomes.
Arimetamycin A: improving clinically relevant families of natural products through sequence-guided screening of soil metagenomes.
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DOI：
10.1002/anie.201305109
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发表时间：
2013-10-11
影响因子：
16.6
通讯作者：
Brady, Sean F.
中科院分区：
文献类型：
--
作者：
Kang, Hahk-Soo;Brady, Sean F.
由于无法培养大多数环境细菌[1]以及在实验室条件下生物合成途径的沉默，天然微生物群落编码的化学多样性受到了严重的限制。[2]据预测，土壤中含有数千种独特的细菌物种，这些细菌物种可能含有数万种功能未开发的天然产物生物合成基因簇。[3]随着宏基因组克隆方法的发展，现在可以使用直接从土壤中提取的DNA（环境DNA，eDNA）构建文库，捕获土壤环境中存在的巨大生物合成多样性。[4]这些库提供了一种功能上检查未开发的土壤生物合成基因簇的手段，因此，序列引导的天然产物发现计划的吸引力资源。[5]基于在饱和土壤eDNA文库中捕获的生物合成多样性的大小，我们认为可以使用这些文库来鉴定具有潜在改善的生物活性的临床相关天然产物家族的新成员。为此，我们使用天然产物序列标签驱动的方法来指导基于蒽环类的芳香族聚酮化合物的发现，与目前临床使用的天然产物蒽环类相比，该芳香族聚酮化合物显示出改善的体外抗增殖活性。在异源表达实验中，发现eDNA衍生的臂簇编码阿瑞霉素A，一种蒽环类抗生素，其比临床上使用的天然蒽环类抗生素更有效，并且保留了对多药耐药（MDR）癌细胞的活性。[6]这些代谢物的生物合成虽然在细节上有所不同，但都起源于由三种蛋白[β-酮脂酰合酶α（KSα）、β-酮脂酰合酶β（KSβ）、酰基载体蛋白（ACP）]组成的保守最小聚酮合酶（min-PKS）产生聚乙酸酯前体（图1）。[6]KSα和KSβ基因进化成与特定芳香族聚酮结构类别密切相关的组，所述芳香族聚酮结构类别由它们所在的基因簇编码。[7]由此推断
The chemical diversity encoded by natural microbial communities has been significantly underexplored due to limitations associated with the inability to culture the majority of environmental bacteria [1] and the silencing of biosynthetic pathways under laboratory conditions.[2] Soils are predicted to contain thousands of unique bacterial species, which potentially harbor tens of thousands of functionally unexplored natural product biosynthetic gene clusters.[3] With the development of metagenomic cloning methods, it is now possible to use DNA extracted directly from soil (environmental DNA, eDNA) to construct libraries that capture the enormous biosynthetic diversity present in soil environments.[4] These libraries provide a means of functionally examining unexplored soil biosynthetic gene clusters and are therefore, appealing resources for sequence guided natural product discovery programs.[5] Based on the magnitude of the biosynthetic diversity captured in saturating soil eDNA libraries, we believed that it would be possible to use these libraries to identify novel members of clinically relevant natural product families with potentially improved biological activities. To this end, we used a natural product sequence-tag driven approach to guide the discovery of an anthracycline-based aromatic polyketide that shows improved in vitro antiproliferative activity compared to the natural product anthracyclines that are currently in clinical use. In heterologous expression experiments the eDNA-derived arm cluster was found to encode for arimetamycin A, an anthracycline that is more potent than clinically used natural anthracyclines and retains activity against multidrug-resistant (MDR) cancer cells.Aromatic polyketides comprise a large class of structurally and functionally diverse bacterial natural products.[6] The biosyntheses of these metabolites, although differing in detail, all originate with the production of a polyacetate precursor by a conserved minimal polyketide synthase (min-PKS) that is composed of three proteins [β-ketoacyl synthase alpha (KSα), βketoacyl synthase beta (KSβ), acyl carrier protein (ACP)](Figure 1).[6] KSα and KSβ genes clade into groups that correlate strongly with the specific aromatic polyketide structural classes that are encoded by the gene clusters in which they reside.[7] Extrapolating from this
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影响因子：
14.8
作者：
Brady, Sean F.
通讯作者：
Brady, Sean F.
影响因子：
1.8
作者：
He, HY;Shen, B;Carter, GT
通讯作者：
Carter, GT
影响因子：
14.8
作者：
Fisch, Katja M.;Gurgui, Cristian;Piel, Joern
通讯作者：
Piel, Joern
影响因子：
4.8
作者：
Hong, HJ;Hutchings, MI;Buttner, MJ
通讯作者：
Buttner, MJ
影响因子：
3.2
作者：
Olano, Carlos;Abdelfattah, Mohamed S.;Salas, Jose A.
通讯作者：
Salas, Jose A.