Sequence-Structure-Function Classification of a Catalytically Diverse Oxidoreductase Superfamily in Mycobacteria
Sequence-Structure-Function Classification of a Catalytically Diverse Oxidoreductase Superfamily in Mycobacteria
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DOI：
10.1016/j.jmb.2015.09.021
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发表时间：
2015-11-06
影响因子：
5.6
通讯作者：
Jackson, Colin J.
中科院分区：
文献类型：
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作者：
Ahmed, F. Hafna;Carr, Paul D.;Jackson, Colin J.
脱氮黄素辅因子F-420在缺氧、氧化应激和抗生素治疗期间增强分枝杆菌的持久性。然而，在这些条件下利用F-420的分枝杆菌酶的身份和功能尚未得到解决。在这项工作中，我们使用序列相似性网络来分析分枝杆菌中最大的F-420依赖蛋白质家族的分布。我们表明，这些酶是一个更大的分裂β桶酶超家族（黄素/脱氮黄素氧化还原酶，FDOR），包括以前的特点吡哆胺/吡哆醇-5 '-磷酸氧化酶和血红素加氧酶的一部分。我们发现，这些蛋白质不同地利用F-420，黄素单核苷酸，黄素腺嘌呤二核苷酸，血红素辅因子。使用系统发育，结构和光谱方法的功能注释揭示了它们参与血红素降解，胆绿素还原，脂肪酸修饰和醌还原。四个新的晶体结构表明，可塑性的底物结合口袋和修改辅因子结合基序，使FDORs进行各种功能。这种系统的分类和分析提供了一个框架，进一步功能分析的作用FDOR在分枝杆菌的发病机制和持久性。(C)2015爱思唯尔有限公司版权所有。
The deazaflavin cofactor F-420 enhances the persistence of mycobacteria during hypoxia, oxidative stress, and antibiotic treatment. However, the identities and functions of the mycobacterial enzymes that utilize F-420 under these conditions have yet to be resolved. In this work, we used sequence similarity networks to analyze the distribution of the largest F-420-dependent protein family in mycobacteria. We show that these enzymes are part of a larger split beta-barrel enzyme superfamily (flavin/deazaflavin oxidoreductases, FDORs) that include previously characterized pyridoxamine/pyridoxine-5'-phosphate oxidases and heme oxygenases. We show that these proteins variously utilize F-420, flavin mononucleotide, flavin adenine dinucleotide, and heme cofactors. Functional annotation using phylogenetic, structural, and spectroscopic methods revealed their involvement in heme degradation, biliverdin reduction, fatty acid modification, and quinone reduction. Four novel crystal structures show that plasticity in substrate binding pockets and modifications to cofactor binding motifs enabled FDORs to carry out a variety of functions. This systematic classification and analysis provides a framework for further functional analysis of the roles of FDORs in mycobacterial pathogenesis and persistence. (C) 2015 Elsevier Ltd. All rights reserved.