Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266, the most potent among them, can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.

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人免疫活性固醇在结核分枝杆菌中的代谢命运

结核分枝杆菌（Mtb）感染是全球十大死亡原因之一，耐药菌株的数量正在增加。Mtb对人类免疫信号分子的直接拦截仍然难以捉摸，限制了药物的发现。氧固醇和类固醇可调节先天和适应性免疫反应。在这里我们报告启动胆固醇分解代谢的Mtb酶的功能，结构和生物信息学研究，并证明它们与人类免疫力的相互关系。我们表明，这些酶代谢人的免疫氧固醇信使。其中最有效的Rv2266也可以代谢维生素D3（VD3）衍生物。高分辨率结构显示了固醇结合的常见模式，并揭示了催化过程中的氧化攻击位点。最后，我们设计了一种结合并抑制三种研究蛋白质的化合物。该化合物对巨噬细胞中的Mtb H37Rv具有活性。我们的发现有助于分子对抑制免疫力的理解，并表明Mtb有其自身的转化系统，类似于人的I期药物代谢系统。