Campbell Christopher T, Sampathkumar Srinivasa-Gopalan, Yarema Kevin J
Department of Biomedical Engineering, The Johns Hopkins University, Clark Hall 106A, Baltimore, MD 21218, USA.
Mol Biosyst. 2007 Mar;3(3):187-94. doi: 10.1039/b614939c. Epub 2007 Jan 12.
Many adhesion and signaling molecules critical for development, as well as surface markers implicated in diseases ranging from cancer to influenza, contain oligosaccharides that modify their functions. Inside a cell, complex glycosylation pathways assemble these oligosaccharides and attach them to proteins and lipids as they traffic to the cell surface. Until recently, practical technologies to manipulate glycosylation have lagged unlike the molecular biologic and genetic methods available to intervene in nucleic acid and protein biochemistry; now, metabolic oligosaccharide engineering shows promise for manipulating glycosylation. In this methodology, exogenously-supplied non-natural sugars intercept biosynthetic pathways and exploit the remarkable ability of many of the enzymes involved in glycosylation to process metabolites with slightly altered chemical structures. To date, non-natural forms of sialic acid, GalNAc, GlcNAc, and fucose have been incorporated into glycoconjugates that appear on the cell surface; in addition O-GlcNAc protein modification involved in intracellular signaling has been tagged with modified forms of this sugar. Reactive functional groups, including ketones, azides, and thiols, have been incorporated into glycoconjugates and thereby provide chemical 'tags' that can be used for diverse purposes ranging from drug delivery to new modes of carbohydrate-based cell adhesion that can be used to control stem cell destiny. Finally, strategies for further engineering non-natural sugars to improve their pharmacological properties and provide complementary biological activities, such as addition of short chain fatty acids, are discussed in this article.
许多对发育至关重要的黏附分子和信号分子，以及涉及从癌症到流感等多种疾病的表面标志物，都含有可修饰其功能的寡糖。在细胞内部，复杂的糖基化途径组装这些寡糖，并在它们运输到细胞表面时将其连接到蛋白质和脂质上。直到最近，与可用于干预核酸和蛋白质生物化学的分子生物学和遗传学方法不同，操纵糖基化的实用技术一直滞后；现在，代谢寡糖工程在操纵糖基化方面显示出前景。在这种方法中，外源供应的非天然糖拦截生物合成途径，并利用许多参与糖基化的酶处理化学结构略有改变的代谢物的非凡能力。迄今为止，非天然形式的唾液酸、N-乙酰半乳糖胺、N-乙酰葡糖胺和岩藻糖已被纳入出现在细胞表面的糖缀合物中；此外，参与细胞内信号传导的O-连接N-乙酰葡糖胺蛋白修饰已用这种糖的修饰形式进行标记。包括酮、叠氮化物和硫醇在内的反应性官能团已被纳入糖缀合物中，从而提供可用于多种目的的化学“标签”，从药物递送 到基于碳水化合物的新型细胞黏附模式，可用于控制干细胞命运。最后，本文讨论了进一步改造非天然糖以改善其药理特性并提供互补生物活性的策略，例如添加短链脂肪酸。
