Wang Xiaoyuan, Quinn Peter J, Yan Aixin
State Key Laboratory of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, China; Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China.
Biol Rev Camb Philos Soc. 2015 May;90(2):408-27. doi: 10.1111/brv.12114. Epub 2014 May 16.
3-deoxy-d-manno-octulosonic acid-lipid A (Kdo2 -lipid A) is the essential component of lipopolysaccharide in most Gram-negative bacteria and the minimal structural component to sustain bacterial viability. It serves as the active component of lipopolysaccharide to stimulate potent host immune responses through the complex of Toll-like-receptor 4 (TLR4) and myeloid differentiation protein 2. The entire biosynthetic pathway of Escherichia coli Kdo2 -lipid A has been elucidated and the nine enzymes of the pathway are shared by most Gram-negative bacteria, indicating conserved Kdo2 -lipid A structure across different species. Yet many bacteria can modify the structure of their Kdo2 -lipid A which serves as a strategy to modulate bacterial virulence and adapt to different growth environments as well as to avoid recognition by the mammalian innate immune systems. Key enzymes and receptors involved in Kdo2 -lipid A biosynthesis, structural modification and its interaction with the TLR4 pathway represent a clear opportunity for immunopharmacological exploitation. These include the development of novel antibiotics targeting key biosynthetic enzymes and utilization of structurally modified Kdo2 -lipid A or correspondingly engineered live bacteria as vaccines and adjuvants. Kdo2 -lipid A/TLR4 antagonists can also be applied in anti-inflammatory interventions. This review summarizes recent knowledge on both the fundamental processes of Kdo2 -lipid A biosynthesis, structural modification and immune stimulation, and applied research on pharmacological exploitations of these processes for therapeutic development.
3-脱氧-D-甘露糖辛酮酸脂A（Kdo2-脂A）是大多数革兰氏阴性菌脂多糖的必需成分，也是维持细菌生存能力的最小结构成分。它作为脂多糖的活性成分，通过Toll样受体4（TLR4）和髓样分化蛋白2的复合物刺激宿主产生强烈的免疫反应。大肠杆菌Kdo2-脂A的整个生物合成途径已被阐明，该途径中的九种酶为大多数革兰氏阴性菌所共有，这表明不同物种间Kdo2-脂A结构具有保守性。然而，许多细菌可以修饰其Kdo2-脂A的结构，这是一种调节细菌毒力、适应不同生长环境以及避免被哺乳动物先天免疫系统识别的策略。参与Kdo2-脂A生物合成、结构修饰及其与TLR4途径相互作用的关键酶和受体为免疫药理学开发提供了明确的机会。这些机会包括开发针对关键生物合成酶的新型抗生素，以及利用结构修饰的Kdo2-脂A或相应工程改造的活细菌作为疫苗和佐剂。Kdo2-脂A/TLR4拮抗剂也可用于抗炎干预。本综述总结了关于Kdo2-脂A生物合成、结构修饰和免疫刺激的基本过程的最新知识，以及这些过程在治疗开发中的药理学应用研究。
