Nitrosopyridine Probe To Detect Polyketide Natural Products with Conjugated Alkenes: Discovery of Novodaryamide and Nocarditriene
Nitrosopyridine Probe To Detect Polyketide Natural Products with Conjugated Alkenes: Discovery of Novodaryamide and Nocarditriene
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DOI：
10.1021/acschembio.8b00598
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发表时间：
2018-11-01
影响因子：
4
通讯作者：
Hughes, Chambers C.
中科院分区：
文献类型：
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作者：
Castro-Falcon, Gabriel;Millan-Aguinaga, Natalie;Hughes, Chambers C.
一种优化的亚硝基为基础的探针，有利于发现共轭含烯烃的天然产物在未加工的提取物。它通过亚硝基-Diels-桤木环化与共轭烯烃发生化学选择性反应，产生具有独特发色团和同位素独特溴原子的衍生物，可以使用液相色谱/质谱和称为MeHaloCoA（海洋卤代化合物分析）的生物信息学工具快速鉴定。当基因组挖掘技术鉴定含有具有两个或更多个重复的KS-AT-DH-KR-ACP结构域序列的聚酮基因簇的菌株时，理想地使用探针，所述重复的KS-AT-DH-KR-ACP结构域序列是共轭烯烃生物合成所需的。比较5溴化芳基亚硝基试剂与模型化合物螺旋霉素，蟾蜍灵，雷帕霉素，利福平的反应性和光谱特性，导致5-溴-2-亚硝基吡啶作为最合适的探针结构的鉴定。然后在细菌提取物中证明了亲二烯体探针的实用性。泰内酯，novodaryamide和daryamide A，哌嗪霉素A，和saccharamonopyrones A和B干净地标记在提取物中从各自的细菌生产者，在高区域选择性，但具有不同程度的非对映选择性。该方法的进一步应用导致从海洋来源的拟诺卡氏菌菌株CNY-503中发现了一种名为诺卡氏三烯的新天然产物，其含有前所未有的环氧-2，3，4，5-四氢吡啶结构。
An optimized nitroso-based probe that facilitates the discovery of conjugated alkene-containing natural products in unprocessed extracts was developed. It chemoselectively reacts with conjugated olefins via a nitroso-Diels-Alder cyclization to yield derivatives with a distinct chromophore and an isotopically unique bromine atom that can be rapidly identified using liquid chromatography/mass spectrometry and a bioinformatics tool called MeHaloCoA (Marine Halogenated Compound Analysis). The probe is ideally employed when genome-mining techniques identify strains containing polyketide gene clusters with two or more repeating KS-AT-DH-KR-ACP domain sequences, which are required for the biosynthesis of conjugated alkenes. Comparing the reactivity and spectral properties of five brominated arylnitroso reagents with model compounds spiramycin, bufalin, rapamycin, and rifampicin led to the identification of 5-bromo-2-nitrosopyridine as the most suitable probe structure. The utility of the dienophile probe was then demonstrated in bacterial extracts. Tylactone, novodaryamide and daryamide A, piperazimycin A, and the saccharamonopyrones A and B were cleanly labeled in extracts from their respective bacterial producers, in high regioselectivity but with varying degrees of diastereoselectivity. Further application of the method led to the discovery of a new natural product called nocarditriene, containing an unprecedented epoxy-2,3,4,5-tetrahydropyridine structure, from marine-derived Nocardiopsis strain CNY-503.