Lingwood Clifford, Sadacharan Skanda, Abul-Milh Maan, Mylvaganum Murugespillai, Peter Marcus
Section of Infection, Immunity, Injury, and Repair, Research Institute, The Hospital for Sick Children, and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Methods Mol Biol. 2006;347:305-20. doi: 10.1385/1-59745-167-3:305.
Despite the extensive structural characterization of glycosphingolipids (GSLs), their functions in cell physiology and pathobiology remain elusive. This is largely owing to the fact that they are difficult to handle, being insoluble in aqueous media, and that no one gene alone determines their synthesis. The heterogeneity of the lipid moiety provides a further confounding factor. GSLs are central components within lipid rafts, which are major foci for transmembrane signaling and interactions between eukaryotic cells and microbial pathogens. GSL receptor function often requires the lipid moiety, and lipid-free sugar analogs are ineffective inhibitors. In order to overcome some of these problems, we have synthesized adamantyl GSL analogs which, in part, mimic GSL membrane receptor function in solution. These compounds are made by replacing the endogenous fatty acid with an adamantan frame. This rigid hydrophobic structure surprisingly increases the water solubility of the conjugate and retains receptor function. These GSL mimics provide probes to study GSL receptor function within cells. They compete with native GSLs for ligand binding and are taken up by cells to potentially alter GSL-mediated interaction. We are focused on two derivatives, adamantyl globotriaosyl ceramide and adamantyl sulfogalactosyl ceramide, and have used these analogs to probe GSL function in microbial pathology and hsp70 function. This chapter describes the syntheses and uses of these mimics.
尽管对糖鞘脂（GSLs）进行了广泛的结构表征，但其在细胞生理学和病理生物学中的功能仍不清楚。这主要是因为它们难以处理，不溶于水性介质，而且没有一个基因单独决定其合成。脂质部分的异质性进一步增加了复杂性。GSLs是脂筏的核心成分，而脂筏是跨膜信号传导以及真核细胞与微生物病原体之间相互作用的主要焦点。GSL受体功能通常需要脂质部分，无脂质的糖类似物是无效的抑制剂。为了克服其中一些问题，我们合成了金刚烷基GSL类似物，其在一定程度上模拟了溶液中的GSL膜受体功能。这些化合物是通过用金刚烷骨架取代内源性脂肪酸制成的。这种刚性疏水结构出人意料地增加了共轭物的水溶性并保留了受体功能。这些GSL模拟物提供了研究细胞内GSL受体功能的探针。它们与天然GSLs竞争配体结合，并被细胞摄取以潜在地改变GSL介导的相互作用。我们专注于两种衍生物，金刚烷基球三糖基神经酰胺和金刚烷基磺基半乳糖基神经酰胺，并已使用这些类似物来探究微生物病理学中的GSL功能和hsp70功能。本章描述了这些模拟物的合成和用途。
