Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones.
Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones.
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DOI：
10.1002/anie.202017086
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发表时间：
2021-04-06
期刊：
影响因子：
--
通讯作者：
Gulder TAM
中科院分区：
文献类型：
--
作者：
Einsiedler M;Jamieson CS;Maskeri MA;Houk KN;Gulder TAM
先前的研究表明，Fe II/α-酮戊二酸依赖性双加氧酶AsqJ诱导构巢曲霉中的维生素B1生物合成中的骨架重排，从苯并[1，4]二氮杂卓-2，5-二酮底物产生喹诺酮骨架。我们报告说，AsqJ催化一个额外的，完全不同的反应，简单地通过在benzodiazepinedione底物的取代基的变化。这一新的机制是通过底物筛选、功能探针的应用和计算分析建立的。AsqJ从合适的苯并[1，4]二氮杂卓-2，5-二酮底物的杂环结构切除H2 CO以生成喹唑啉酮。这种新的AsqJ催化途径由复杂底物内的单个取代基控制。AsqJ的这种独特的底物导向反应性能够靶向生物催化生成喹诺酮或喹唑啉酮，这两种生物碱框架具有特殊的生物医学意义。AsqJ催化喹诺酮生物合成中的复杂重排序列。我们表明AsqJ生物催化潜力显着超过这一自然功能。发现了一种前所未有的导致喹唑啉酮的反应途径，详细地功能和机理表征，揭示了酶催化中独特的底物依赖性产物选择性。
Previous studies showed that the FeII/α‐ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine‐2,5‐dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine‐2,5‐dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate‐directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance. AsqJ catalyzes a complex rearrangement sequence in quinolone biosynthesis. We show the AsqJ biocatalytic potential to significantly exceed this natural function. An unprecedented reaction pathway leading to quinazolinones is uncovered, functionally and mechanistically characterized in detail, revealing a unique substrate‐dependent product selectivity in enzyme catalysis.
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影响因子：
16.6
作者：
Kishimoto S;Hara K;Hashimoto H;Hirayama Y;Champagne PA;Houk KN;Tang Y;Watanabe K
通讯作者：
Watanabe K
影响因子：
2.1
作者：
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通讯作者：
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影响因子：
1.8
作者：
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通讯作者：
Al-Said, Naim H.
影响因子：
16.6
作者：
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通讯作者：
Kaila VRI
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD