The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress.
The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress.
复制标题
DOI：
10.1371/journal.ppat.1011441
复制
发表时间：
2023-06
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
沙门氏菌在天然宿主反应中受到吞噬细胞NADPH氧化酶产生的活性氧的细胞毒性作用。周质超氧化物歧化酶、过氧化氢酶和过氧化氢酶对吞噬细胞呼吸爆发中合成的超氧化物歧化酶和过氧化氢(H_2O_2)进行解毒。谷胱甘肽还有助于沙门氏菌对抗吞噬细胞的NADPH氧化酶；然而，这种低分子硫醇提高沙门氏菌对氧化应激的抵抗力的分子机制目前尚不清楚。我们在此报道，经历氧化应激的沙门氏菌在转录和功能上激活了从糖酵解分支出来的甲基乙二醛途径。在暴露于过氧化氢后，甲基乙二醛途径的激活消耗了沙门氏菌中谷胱甘肽还原能力的很大比例。甲基乙二醛途径使沙门氏菌能够平衡葡萄糖利用和有氧呼吸输出。沙门氏菌利用与谷胱甘肽消耗甲基乙醛途径相关的代谢灵活性来抵抗巨噬细胞和小鼠吞噬细胞NADPH氧化酶的酶活性产生的活性氧物种。综上所述，谷胱甘肽通过促进甲基乙醛途径(糖酵解的一种分支代谢适应)，培养沙门氏菌对吞噬细胞NADPH氧化酶的抗微生物作用的氧化应激抵抗力。低分子量硫醇，如三肽谷胱甘肽，是不同系统发育生物抗氧化剂武器库的重要组成部分。承受过氧化应激的沙门氏菌在还原型谷胱甘肽池中的数量急剧减少。然而，谷胱甘肽还原能力的下降并不能与过氧化氢直接氧化三肽所预期的氧化谷胱甘肽的积累相提并论。谷胱甘肽合成酶的参与，而不是还原氧化型谷胱甘肽的谷胱甘肽氧化还原酶的参与，使人们进一步怀疑这种低分子硫醇在沙门氏菌发病中作为活性氧物种清除剂的作用。我们的研究表明，持续氧化应激的沙门氏菌在甲基乙醛途径中消耗大量的谷胱甘肽，该途径在氧化应激期间被激活，因为溢出代谢是有利的。乙二醛途径中乙醛酶II的乳酸基谷胱甘肽水解酶活性允许沙门氏菌在葡萄糖中生长，同时促进有氧呼吸。综上所述，谷胱甘肽对沙门氏菌抗氧化性的贡献主要来源于代谢副产物乙醛的亲电解毒作用，而不是通过过氧化氢过氧键的直接亲核攻击而起到清除活性氧的作用。
Salmonella suffer the cytotoxicity of reactive oxygen species generated by the phagocyte NADPH oxidase in the innate host response. Periplasmic superoxide dismutases, catalases and hydroperoxidases detoxify superoxide and hydrogen peroxide (H2O2) synthesized in the respiratory burst of phagocytic cells. Glutathione also helps Salmonella combat the phagocyte NADPH oxidase; however, the molecular mechanisms by which this low-molecular-weight thiol promotes resistance of Salmonella to oxidative stress are currently unknown. We report herein that Salmonella undergoing oxidative stress transcriptionally and functionally activate the methylglyoxal pathway that branches off from glycolysis. Activation of the methylglyoxal pathway consumes a substantial proportion of the glutathione reducing power in Salmonella following exposure to H2O2. The methylglyoxal pathway enables Salmonella to balance glucose utilization with aerobic respiratory outputs. Salmonella take advantage of the metabolic flexibility associated with the glutathione-consuming methylglyoxal pathway to resist reactive oxygen species generated by the enzymatic activity of the phagocyte NADPH oxidase in macrophages and mice. Taken together, glutathione fosters oxidative stress resistance in Salmonella against the antimicrobial actions of the phagocyte NADPH oxidase by promoting the methylglyoxal pathway, an offshoot metabolic adaptation of glycolysis. Low-molecular-weight thiols such as the tripeptide glutathione are essential components of the antioxidant arsenal of phylogenetically diverse organisms. Salmonella undergoing peroxide stress suffer a dramatic diminution in the pool of reduced glutathione. However, drops in glutathione reducing power are not paralleled with a buildup of oxidized glutathione that would be expected by direct oxidation of the tripeptide by H2O2. The involvement of glutathione synthetase, but not glutathione oxidoreductase that reduces oxidized glutathione, casts further doubt on the role of this low-molecular-weight thiol as scavenger of reactive oxygen species in Salmonella pathogenesis. Our investigations herein show that Salmonella sustaining oxidative stress consume large amounts of glutathione in the methylglyoxal pathway that is activated as overflow metabolism is favored during periods of oxidative stress. The lactoylglutathione hydrolase activity of glyoxalase II in the methylglyoxal pathway allows Salmonella to grow in glucose, while simultaneously fostering aerobic respiration. In conclusion, the contribution of glutathione to the resistance of Salmonella to oxidative stress mostly stems from the electrophilic detoxification of aldehyde byproducts of metabolism rather than serving as a scavenger of reactive oxygen species via direct nucleophilic attack of H2O2 peroxo linkage.
登录
查看更多内容
影响因子：
15.3
作者：
Mastroeni, P;Vazquez-Torres, A;Fang, F C;Xu, Y;Khan, S;Hormaeche, C E;Dougan, G
通讯作者：
Dougan, G
DOI：
10.3390/antiox11102053
发表时间：
2022-10-18
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
168.9
作者：
Feasey, Nicholas A.;Dougan, Gordon;Kingsley, Robert A.;Heyderman, Robert S.;Gordon, Melita A.
通讯作者：
Gordon, Melita A.
影响因子：
15.9
作者：
BUCHMEIER, NA;LIBBY, SJ;FANG, FC
通讯作者：
FANG, FC
影响因子：
4.8
作者：
Henard, Calvin A.;Bourret, Travis J.;Vazquez-Torres, Andres
通讯作者：
Vazquez-Torres, Andres