117(P-68) 標識化lipid Aの合成と受容体との相互作用研究(ポスター発表の部)

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Lipid A is the active component of lipopolysaccharide (LPS), which is a constituent of the outer membrane of Gram-negative bacteria and is also known as endotoxin for its potent immunostimulation and toxic function. Recent discoveries in innate immune system have shown the mechanism of immunostimulation by microbial components via toll-like receptors (TLRs). One of those receptors, Toll like receptor 4 (TLR4), is responsible for the recognition of LPS and lipid A. In order to understand the molecular mechanism of LPS recognition via TLR4, we synthesized fluorescence-labeled, biotin-labeled, and tritium-labeled lipid A. By establishing a new method for synthesis of labeled bioactive lipid A, where glucose residue was used for both tag and a hydrophilic linker for labeling. Hydrophilic and anionic fluorescent groups were used for labeling to prevent self-aggregation by hydrophobic interaction. The glucose tag was introduced via a glutaric acid linker to the 6'-position of lipid A, which is the position of connection with polysaccharide in LPS. Labeling groups were introduced to the glucose residue via the formation of a hydrazone under mild conditions. Several fluorescence-labeled and biotin-labeled lipid As were efficiently synthesized without any damage to the phosphoryl and acyl groups. Alexa Fluor 568^<TM>-labeled E. coli-type lipid A thus prepared showed strong fluorescence and bioactivity. We have also synthesized radioactive tritium-labeled lipid A in a different rout. With these labeled compounds, we demonstrated that TLR4-MD2 complex directly recognizes LPS and lipid A (E.coli-type) to induce oligomerization of TLR4-MD2. The antagonistic biosynthetic precursor of lipid A (lipid A IVa) binds to TLR4-MD2 but does not trigger TLR4 oligomerization, suggesting the importance of the receptor TLR4 oligomerization for the signal transduction.
天然有機化合物討論会の論文
2004-10-01

117(P-68) 標識化lipid Aの合成と受容体との相互作用研究(ポスター発表の部)

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