The structure of flavin-dependent tryptophan 7-halogenase RebH
The structure of flavin-dependent tryptophan 7-halogenase RebH
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DOI：
10.1002/prot.21627
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发表时间：
2008-01-01
影响因子：
2.9
通讯作者：
Phillips, George N., Jr.
中科院分区：
文献类型：
--
作者：
Bitto, Eduard;Huang, Yu;Phillips, George N., Jr.
酶催化的区域和立体卤化反应提高了一系列具有重要治疗作用的天然产物的生物活性，包括抗生素万古霉素和氯霉素以及抗癌药物Calicheamicin和rebecamycin。1-5负责这一具有挑战性的合成反应的主要酶类，依赖于Avin的卤化酶，利用Avin、卤离子(氯、溴或碘)和0.6催化碳-卤键的形成。6最近在模型依赖于Avin的色氨酸7-卤化酶PRNA和RebH7-10方面取得的机理和结构进展极大地提高了对这一独特反应的理解水平。根据这些研究，色氨酸卤化的机理是通过FAD(C4a)HOClOOH激活氯离子进入瞬时氯化物种。11-14需要瞬时氯化物种的关键证据是发现了一条∼10？长的隧道，将配体结合形式的PRNAFAD和色氨酸分开。12在最近一项引人注目的研究中，为了阐明REBH控制这种高活性和不分青红皂白的氧化剂的策略，一种Lys79-ϵNH-Cl氯胺中间体被牵连为REBH中的实际氯化物种，并报告了REBH的结构研究。在这里，我们报告了我们对Lechvalieria Aerocoloniges Rebh(UniProt加入)的独立结构分析
Enzyme catalyzed regio-and stereo-speci c halogenations in uence the biological activity of a diverse array of therapeutically important natural products, including the antibiotics vancomycin and chloramphenicol as well as the anticancer agents calicheamicin and rebeccamycin. 1-5 The major class of enzymes responsible for this challenging synthetic reaction, the avin-dependent halogenases, catalyzes the formation of carbon-halogen bonds using avin, a halide ion (Cl, Br or I), and O. 6 Recent mechanistic and structural advances achieved with the model avin-dependent tryptophan 7-halogenases PrnA and RebH7-10 have greatly enhanced the level of understanding of this unique reaction. According to these studies, the mechanism for tryptophan halogenation proceeds via FAD (C4a) OOH activation of a chloride ion into the transient chlorinating species HOCl. 11-14 The key evidence for the requirement of a transient chlorinating species is the discovery that a∼ 10-Å-long tunnel separates FAD and tryptophan in the ligand-bound form of PrnA. 12 In a recent compelling study to elucidate the strategy by which RebH controls this highly reactive and indiscriminant oxidant, a Lys79-ϵNH-Cl chloramine intermediate was implicated as the actual chlorinating species within RebH and a structural investigation of RebH was reported. 10 Here we report our independent structural analysis of Lechevalieria aerocolonigenes RebH (UniProt accession