Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore.
NTU Institute of Structural Biology, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Republic of Singapore.
Sci Rep. 2017 Jul 11;7(1):5159. doi: 10.1038/s41598-017-05354-5.
Despite the highly oxidative environment of the phagosomal lumen, the need for maintaining redox homeostasis is a critical aspect of mycobacterial biology. The pathogens are equipped with the sophisticated thioredoxin- (Trx) and peroxiredoxin system, including TrxC and the alkyl hydroperoxide reductase subunit C (AhpC), whereby TrxC is one of the reducing partners of AhpC. Here we visualize the redox modulated dodecamer ring formation of AhpC from Mycobacterium bovis (BCG strain; MbAhpC) using electron microscopy and present novel insights into the unique N-terminal epitope (40 residues) of mycobacterial AhpC. Truncations and amino acid substitutions of residues in the unique N-terminus of MbAhpC provide insights into their structural and enzymatic roles, and into the evolutionary divergence of mycobacterial AhpC versus that of other bacteria. These structural details shed light on the epitopes and residues of TrxC which contributes to its interaction with AhpC. Since human cells lack AhpC, the unique N-terminal epitope of mycobacterial AhpC as well as the MbAhpC-TrxC interface represent an ideal drug target.
尽管吞噬体腔中存在高度氧化的环境，但维持氧化还原平衡是分枝杆菌生物学的一个关键方面。病原体配备了复杂的硫氧还蛋白-（Trx）和过氧化物酶系统，包括 TrxC 和烷基氢过氧化物还原酶亚基 C（AhpC），其中 TrxC 是 AhpC 的还原伴侣之一。在这里，我们使用电子显微镜可视化了来自牛分枝杆菌（BCG 株；MbAhpC）的 AhpC 的氧化还原调节的十二聚体环形成，并提供了有关分枝杆菌 AhpC 的独特 N 端表位（40 个残基）的新见解。MbAhpC 独特 N 端的截断和氨基酸取代提供了对其结构和酶作用以及分枝杆菌 AhpC 与其他细菌的进化分歧的深入了解。这些结构细节阐明了与 AhpC 相互作用的 TrxC 的表位和残基。由于人类细胞缺乏 AhpC，因此分枝杆菌 AhpC 的独特 N 端表位以及 MbAhpC-TrxC 界面代表了理想的药物靶标。
