Fungal-derived brevianamide assembly by a stereoselective semipinacolase
Fungal-derived brevianamide assembly by a stereoselective semipinacolase
复制标题
通过立体选择性半频那醇酶组装真菌衍生的布雷维亚酰胺
DOI：
10.1038/s41929-020-0454-9
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发表时间：
2020
期刊：
影响因子：
37.8
通讯作者：
Paton
中科院分区：
文献类型：
--
作者：
Ye Ying;Du Lei;Zhang Xingwang;Newmister Sean A.;McCauley Morgan;Alegre-Requena Juan V;Zhang Wei;Mu Shuai;Minami Atsushi;Fraley Amy E.;Adrover-Castellano Maria L.;Carney Nolan A.;Shende Vikram V.;Qi Feifei;Oikawa Hideaki;Kato Hikaru;Tsukamoto Sachiko;Paton
真菌双环[2.2.2]二氮杂辛烷吲哚生物碱是一类重要的天然产物，具有广泛的生物活性。虽然仿生全合成的代表性化合物已被报道，其生物起源的细节，特别是非对映异构体不同和对映异构体antipodal代谢产物的组装机制，仍然在很大程度上未被表征。Brevianamide A代表带有二氧代哌嗪核和罕见的3-螺-β-吲哚基骨架的亚家族的基本形式。本研究对短密青霉Penicillium brevicompactum NRRL 864中短青霉酰胺A的生物合成基因簇进行了鉴定，并阐明了短青霉酰胺A的代谢途径。BvnE被揭示为指定天然产物的选择性生产的必需异构酶/半频哪醇酶。BvnE的结构解析、分子建模和突变分析以及量子化学计算提供了对短藤酰胺A中3-螺-β-吲哚基部分的非对映选择性形成的机理见解。这通过BvnE控制的半频哪醇重排和随后的自发分子内[4 + 2]杂-Diels-桤木环加成反应发生。
Fungal bicyclo[2.2.2]diazaoctane indole alkaloids represent an important family of natural products with a wide spectrum of biological activities. Although biomimetic total syntheses of representative compounds have been reported, the details of their biogenesis, especially the mechanisms for the assembly of diastereomerically distinct and enantiomerically antipodal metabolites, have remained largely uncharacterized. Brevianamide A represents a basic form of the subfamily bearing a dioxopiperazine core and a rare 3-spiro-ψ-indoxyl skeleton. In this study, we have identified the brevianamide A biosynthetic gene cluster fromPenicillium brevicompactumNRRL 864 and elucidated the metabolic pathway. BvnE was revealed to be an essential isomerase/semipinacolase that specifies the selective production of the natural product. Structural elucidation, molecular modelling and mutational analysis of BvnE as well as quantum chemical calculations have provided mechanistic insights into the diastereoselective formation of the 3-spiro-ψ-indoxyl moiety in brevianamide A. This occurs through a BvnE-controlled semipinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels–Alder cycloaddition.