Activity-based probes for studying the activity of flavin-dependent oxidases and for the protein target profiling of monoamine oxidase inhibitors.
Activity-based probes for studying the activity of flavin-dependent oxidases and for the protein target profiling of monoamine oxidase inhibitors.
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DOI：
10.1002/anie.201201955
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发表时间：
2012-07-09
影响因子：
16.6
通讯作者：
Breinbauer, Rolf
中科院分区：
文献类型：
--
作者：
Krysiak, Joanna M.;Kreuzer, Johannes;Macheroux, Peter;Hermetter, Albin;Sieber, Stephan A.;Breinbauer, Rolf
基于活性的蛋白质谱分析（ABPP）已经成为一种强大的化学蛋白质组学技术，允许在其天然细胞环境中解剖复杂的配体-蛋白质相互作用。[1]基于小分子活性的探针在细胞水平上询问酶活性的应用已经导致了参与癌症的蛋白质的鉴定和功能表征，[2]信号通路，[3]微生物发病机制和毒力，[4]宿主-病毒相互作用，[5]和其他生物过程。然而，到目前为止，大多数ABPP研究都针对具有完善的催化机制和参与与活性探针形成共价键的亲核活性位点残基的酶类别（例如丝氨酸水解酶，[6]半胱氨酸[7]和苏氨酸蛋白酶[8]）。因此，ABPP中的一个重要挑战是将探针分子库扩展到具有更复杂催化活性的酶类别，例如激酶，[3，9]转移酶[10]和氧化还原酶[11]，以扩大蛋白质组覆盖范围。在这里，我们介绍了前所未有的活性为基础的一组重要的氧化还原酶，即黄素依赖性oxidases.Flavin-dependent酶催化的各种各样的反应，包括氧化，单加氧，还原，卤化，使他们不可或缺的许多细胞过程。[12]其中，黄素依赖性氧化酶代表了一个复杂的亚类，通过使用分子氧作为电子受体来氧化广谱分子。[13]它们固有的结构多样性、可接受底物的多样性以及活性位点中保守残基的缺乏使得它们难以通过已建立的基因组、结构和蛋白质组学分析进行功能注释。[14]相比之下，ABPP可以作为一个强大的和简单的替代这些酶的全球概况。我们设想，选择性的活性为基础的探针可以建立在简单的原则上的结合亲和力的氧化活化的探针对黄素辅因子，唯一共同的和内在的特征黄素依赖性氧化酶。[第十五条]
Activity-based protein profiling (ABPP) has become a powerful chemical proteomic technology allowing the dissection of complex ligand–protein interactions in their native cellular environment.[1] The application of small-molecule activitybased probes to interrogate enzyme activity on the cell level has led to the identification and functional characterization of proteins involved in cancer,[2] signaling pathways,[3] microbial pathogenesis and virulence,[4] host–virus interactions,[5] and other biological processes. However, up to now most ABPP studies have aimed at enzyme classes with well-established catalytic mechanisms and nucleophilic active-site residues participating in the formation of a covalent bond to activitybased probes (eg serine hydrolases,[6] cysteine [7] and threonine proteases [8]). Thus, one important challenge in ABPP is expanding the pool of probe molecules to enzyme classes with more complex catalytic activities such as kinases,[3, 9] transferases,[10] and oxidoreductases [11] to extend the proteome coverage. Here, we introduce unprecedented activity-based probes for an important group of oxidoreductases, namely flavin-dependent oxidases.Flavin-dependent enzymes catalyze a diverse set of reactions encompassing oxidations, monooxygenations, dehydrogenations, reductions, and halogenations, making them indispensable for many cellular processes.[12] Among them, flavin-dependent oxidases represent a complex subgroup that oxidize a broad spectrum of molecules by the employment of molecular oxygen as an electron acceptor.[13] Their intrinsic structural diversity, multiplicity of accepted substrates, and lack of conserved residues in the active site make them elusive to functional annotation by established genomic, structural, and proteomic analyses.[14] In contrast, ABPP could serve as a powerful and simple alternative for global profiling of these enzymes. We envisioned that selective activity-based probes could be built on the simple principle of the binding affinity of the oxidatively activated probes towards the flavin cofactor, the only common and intrinsic feature of flavin-dependent oxidases.[15]
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影响因子：
2.9
作者：
Edmondson, Dale E.;Binda, Claudia;Wang, Jin;Upadhyay, Anup K.;Mattevi, Andrea
通讯作者：
Mattevi, Andrea
影响因子：
56.9
作者：
FOWLER, JS;MACGREGOR, RR;LANGSTROM, B
通讯作者：
LANGSTROM, B
影响因子：
3.4
作者：
Edmondson, DE;Binda, C;Mattevi, A
通讯作者：
Mattevi, A
影响因子：
16.1
作者：
Bortolato, Marco;Chen, Kevin;Shih, Jean C.
通讯作者：
Shih, Jean C.
影响因子：
15
作者：
Eirich, Juergen;Orth, Ronald;Sieber, Stephan A.
通讯作者：
Sieber, Stephan A.