Lipid structure influences the ability of glucose monocorynomycolate to signal through Mincle
Lipid structure influences the ability of glucose monocorynomycolate to signal through Mincle
复制标题
脂质结构影响葡萄糖单棒菌酸酯通过 Mincle 发出信号的能力
DOI：
10.1039/c6ob01781a
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发表时间：
2016
影响因子：
3.2
通讯作者：
Spencer J. Williams
中科院分区：
文献类型：
--
作者：
Phillip L. van der Peet;Masahiro Nagata;Sayali Shah; Jonathan M. White;Sho Yamasaki;Spencer J. Williams
Mincle（巨噬细胞诱导的C型凝集素）是一种C型凝集素受体，具有免疫感应一系列病原体和共生体衍生糖脂的能力。Mincle可以识别来自分枝杆菌和棒状杆菌的海藻糖、甘油和葡萄糖的分枝菌酸酯和/或棒状分枝菌酸酯。虽然简单的直链长脂肪酸（例如山嵛酸）可以取代海藻糖和甘油上的分枝菌酸，并通过Mincle维持稳健的信号传导，但据报道，葡萄糖单山嵛酸酯的活性远低于葡萄糖单紫茉莉酸酯（GMCM）。我们报告了一系列GMCM类似物的制备，以探索通过Mincle进行信号传导的脂质链中的结构要求。携带简单的直链或支链脂肪酸酯的GMCM类似物通过人和小鼠Mincle仅提供弱信号传导。具有截短（戊基）α链的GMCM变体提供减弱的信号传导，而具有延长（二十三烷基; C23）α链的类似物与GMCM一样有效地发出信号。这项工作表明，Mincle有能力调查放线菌的分枝菌衍生的糖脂，区分非致病性（如红球菌属）。和基于α链长度的致病性（例如结核分枝杆菌）物种。最后，GMCM的α-苯基十二烷基类似物具有与GMCM相似的效力，仅略低于海藻糖二霉菌酸酯（脐带因子），表明α链中可耐受大官能团。
Mincle (macrophage-inducible C-type lectin) is a C-type lectin receptor that provides the capacity for immune sensing of a range of pathogen- and commensal-derived glycolipids. Mincle can recognize mycolic and/or corynomycolic acid esters of trehalose, glycerol and glucose from mycobacteria and corynebacteria. While simple straight-chain long fatty acids (e.g. behenic acid) can substitute for mycolic acid on trehalose and glycerol and maintain robust signalling through Mincle, glucose monobehenate has been reported to be much less active than glucose monocorynomycolate (GMCM). We report the preparation of a range of analogues of GMCM to explore structural requirements in the lipid chain for signalling through Mincle. GMCM analogues bearing simple straight chain or branched fatty acid esters provided only weak signalling through human and mouse Mincle. A GMCM variant with a truncated (pentyl) α-chain provided attenuated signalling, whereas an analogue with an extended (tricosyl; C23) α-chain signalled as potently as GMCM. This work suggests that Mincle has the ability to survey mycolate-derived glycolipids from actinomycetes, distinguishing non-pathogenic (e.g. Rhodococcus spp.) and pathogenic (e.g. Mycobacterium tuberculosis) species on the basis of α-chain length. Finally, an α-phenyldodecyl analogue of GMCM possessed similar potency to GMCM and was only slightly less potent than trehalose dimycolate (cord factor), showing that large functional groups may be tolerated in the α-chain.