Designed, Flavin-Based Multistate Catalysis

设计的基于黄素的多态催化

• 批准号: 449165398
• 负责人: Dr. Golo Trutz Benjamin Storch
• 金额: --
• 依托单位: Lehrstuhl für Organische Chemie I
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/449165398?language=en
• 关键词: Designed; Flavin; Based; Multistate; Catalysis

Flavoenzymes catalyze highly diverse transformations ranging from oxygenations with oxygen and carbohydrate transfer to oxidations as well as reductions both upon and without visible light excitation. However, these reactions are mediated by the same isoalloxazine reactive site of the flavin adenine dinucleotide (FAD) cofactor. The latter easily changes between oxidation states and covalent substrate adduct states, each of which is characterized by distinct reactivity. In enzymes, control over divergent activity as well as selectivity relies on non-covalent contacts of the isoalloxazine and the substrates with the peptide surrounding. Most flavin activity, therefore, is lost when the isolated cofactor is removed from the peptide surrounding. On the other hand, artificial flavoenzymes are sensitive towards solvent choice and modifications of the isoalloxazine for non-natural reactivity. In this research programme, designed molecular flavin catalysts are proposed in order to make the full spectrum of natural as well as non-natural flavin reactivity accessible. Our key strategy relies on precise tuning of the isoalloxazine reactive center and its three-dimensional ‘outer-sphere’ by means of non-covalent interaction sites, thereby controlling catalyst reactivity and selectivity. Three distinct reactivity areas have been selected based on enzyme activity and the aim for synthetic utility: i) Activation of oxygen from air for hydroxylation and halogenation reactions, ii) organocatalytic glycosylation and oxidative coupling reactions, and iii) decarboxylative peptide conjugation and stapling as well as olefin coupling via visible light excitation of the flavin. Switching between these areas of reactivity - with an identical flavin catalyst - will be accomplished through changing external parameters such as air versus argon atmosphere, oxidative versus reductive conditions, and irradiation versus reaction in the dark. This strategy lays the foundation for multistate reaction sequences, in which a single flavin-based catalyst performs various different transformations consecutively. These multistate catalysts will be applied in stereo-, site-, and chemoselective editing of increasingly complex natural products. Here, the outlined diverse reactivity allows for a variety of modifications including modulation of secondary structure and polarity, attachment of labels, and binding site changes. Recent work in diversification of natural product antibiotics revealed synergistic effects of multiple instead of isolated alterations. In this context, the selective modification of multiple sites - or consecutive editing of a single site - with one designed flavin catalyst is anticipated to be beneficial for accessing biologically relevant complex molecules.

黄素酶催化高度多样化的转化，从含氧和碳水化合物转移到氧化以及在可见光激发下和没有可见光激发下的还原。然而，这些反应由黄素腺嘌呤二核苷酸（FAD）辅因子的相同异咯嗪反应位点介导。后者很容易在氧化态和共价底物加合物态之间变化，每种状态的特征在于不同的反应性。在酶中，对趋异活性以及选择性的控制依赖于异咯嗪和底物与周围肽的非共价接触。因此，当分离的辅因子从肽周围除去时，大多数黄素活性丧失。另一方面，人工黄素酶对溶剂选择和异咯嗪的非天然反应性修饰敏感。在这项研究计划中，提出了设计的分子黄素催化剂，以使天然和非天然黄素反应性的全谱。我们的关键策略依赖于通过非共价相互作用位点精确调节异咯嗪反应中心及其三维“外层”，从而控制催化剂的反应性和选择性。根据酶活性和合成用途的目的，选择了三个不同的反应区域：i）活化空气中的氧气进行羟基化和卤化反应，ii）有机催化糖基化和氧化偶联反应，以及iii）脱羧肽缀合和装订以及通过可见光激发黄素的烯烃偶联。在这些反应区域之间的切换-使用相同的黄素催化剂-将通过改变外部参数来实现，例如空气与氩气气氛，氧化与还原条件，以及在黑暗中照射与反应。这种策略为多状态反应序列奠定了基础，其中单个基于黄素的催化剂连续进行各种不同的转化。这些多状态催化剂将被应用于日益复杂的天然产物的立体编辑，位点编辑和化学选择性编辑。在这里，所概述的不同反应性允许各种修饰，包括二级结构和极性的调节、标记的附着和结合位点的变化。天然产物抗生素多样化的最新工作揭示了多种而不是孤立改变的协同效应。在这种情况下，用一种设计的黄素催化剂对多个位点进行选择性修饰-或对单个位点进行连续编辑-预计有利于获得生物学相关的复杂分子。