PDF(Pubmed)
Abstract：
Mycobacterium tuberculosis (Mtb), the pathogenic bacterium that causes tuberculosis, has evolved sophisticated defense mechanisms to counteract the cytotoxicity of reactive oxygen species (ROS) generated within host macrophages during infection. The melH gene in Mtb and Mycobacterium marinum (Mm) plays a crucial role in defense mechanisms against ROS generated during infection. We demonstrate that melH encodes an epoxide hydrolase and contributes to ROS detoxification. Deletion of melH in Mm resulted in a mutant with increased sensitivity to oxidative stress, increased accumulation of aldehyde species, and decreased production of mycothiol and ergothioneine. This heightened vulnerability is attributed to the increased expression of whiB3, a universal stress sensor. The absence of melH also resulted in reduced intracellular levels of NAD+, NADH, and ATP. Bacterial growth was impaired, even in the absence of external stressors, and the impairment was carbon source dependent. Initial MelH substrate specificity studies demonstrate a preference for epoxides with a single aromatic substituent. Taken together, these results highlight the role of melH in mycobacterial bioenergetic metabolism and provide new insights into the complex interplay between redox homeostasis and generation of reactive aldehyde species in mycobacteria.
OBJECTIVE: This study unveils the pivotal role played by the melH gene in Mycobacterium tuberculosis and in Mycobacterium marinum in combatting the detrimental impact of oxidative conditions during infection. This investigation revealed notable alterations in the level of cytokinin-associated aldehyde, para-hydroxybenzaldehyde, as well as the redox buffer ergothioneine, upon deletion of melH. Moreover, changes in crucial cofactors responsible for electron transfer highlighted melH\'s crucial function in maintaining a delicate equilibrium of redox and bioenergetic processes. MelH prefers epoxide small substrates with a phenyl substituted substrate. These findings collectively emphasize the potential of melH as an attractive target for the development of novel antitubercular therapies that sensitize mycobacteria to host stress, offering new avenues for combating tuberculosis.
OBJECTIVE: This study unveils the pivotal role played by the melH gene in Mycobacterium tuberculosis and in Mycobacterium marinum in combatting the detrimental impact of oxidative conditions during infection. This investigation revealed notable alterations in the level of cytokinin-associated aldehyde, para-hydroxybenzaldehyde, as well as the redox buffer ergothioneine, upon deletion of melH. Moreover, changes in crucial cofactors responsible for electron transfer highlighted melH\'s crucial function in maintaining a delicate equilibrium of redox and bioenergetic processes. MelH prefers epoxide small substrates with a phenyl substituted substrate. These findings collectively emphasize the potential of melH as an attractive target for the development of novel antitubercular therapies that sensitize mycobacteria to host stress, offering new avenues for combating tuberculosis.
摘要：
结核分枝杆菌(Mtb),引起结核病的致病菌，已经进化出复杂的防御机制来抵消感染过程中宿主巨噬细胞内产生的活性氧（ROS）的细胞毒性。Mtb和marinum分枝杆菌（Mm）中的melH基因在针对感染过程中产生的ROS的防御机制中起着至关重要的作用。我们证明melH编码环氧化物水解酶并有助于ROS解毒。Mm中melH的缺失导致对氧化应激敏感性增加的突变体，增加醛物种的积累，并减少了分枝杆菌硫醇和麦角硫因的产生。这种增加的脆弱性归因于通用应力传感器whiB3的表达增加。melH的缺失也导致NAD+的细胞内水平降低,NADH,和ATP。细菌生长受损，即使在没有外部压力的情况下，损害是碳源依赖性的。最初的MelH底物特异性研究表明优选具有单个芳族取代基的环氧化物。一起来看,这些结果强调了melH在分枝杆菌生物能量代谢中的作用,并为分枝杆菌中氧化还原稳态与反应性醛种类生成之间复杂的相互作用提供了新的见解.
目的：本研究揭示了结核分枝杆菌和marinum分枝杆菌melH基因在对抗感染过程中氧化条件的有害影响中的关键作用。这项研究揭示了细胞分裂素相关醛水平的显著变化，对羟基苯甲醛，以及氧化还原缓冲液麦角硫因，删除melh。此外，负责电子转移的关键辅因子的变化强调了melH在维持氧化还原和生物能量过程的微妙平衡方面的关键作用。MelH优选具有苯基取代的底物的环氧化物小底物。这些发现共同强调了melH作为开发新型抗结核疗法的有吸引力的靶标的潜力，该疗法使分枝杆菌对宿主应激敏感。为抗击结核病提供了新的途径。
目的：本研究揭示了结核分枝杆菌和marinum分枝杆菌melH基因在对抗感染过程中氧化条件的有害影响中的关键作用。这项研究揭示了细胞分裂素相关醛水平的显著变化，对羟基苯甲醛，以及氧化还原缓冲液麦角硫因，删除melh。此外，负责电子转移的关键辅因子的变化强调了melH在维持氧化还原和生物能量过程的微妙平衡方面的关键作用。MelH优选具有苯基取代的底物的环氧化物小底物。这些发现共同强调了melH作为开发新型抗结核疗法的有吸引力的靶标的潜力，该疗法使分枝杆菌对宿主应激敏感。为抗击结核病提供了新的途径。
