Expanding the diversity of unnatural cell-surface sialic acids
Expanding the diversity of unnatural cell-surface sialic acids
复制标题
DOI：
10.1002/cbic.200300789
复制
发表时间：
2004-03-05
期刊：
影响因子：
3.2
通讯作者：
Bertozzi, CR
中科院分区：
文献类型：
--
作者：
Luchansky, SJ;Goon, S;Bertozzi, CR
通过代谢寡糖工程可以将新的化学反应性引入细胞表面。[1,2]该技术利用细胞生物合成酶的底物杂乱性，将带有生物正交官能团的非天然单糖传递到细胞聚糖中。例如，n -乙酰甘露糖胺（ManNAc）的衍生物通过细胞生物合成机制转化为相应的唾液酸，随后以唾液糖缀合物的形式传递到细胞表面（图1A）。n -乙酰氨基葡萄糖（GlcNAc）和n -乙酰半乳糖胺（GalNAc）的类似物也被代谢并结合到细胞表面聚糖中，可能分别通过唾液酸和GalNAc回收途径。[3-6]此外，GlcNAc类似物可以取代β-O-GlcNAc残基并入核细胞质蛋白这些途径被用来将独特的亲电试剂如酮和叠氮化物整合到目标糖缀合物类中。这些官能团可以分别通过与肼类化合物[8]缩合和Staudinger连接[9]以化学选择性的方式进一步细化，从而将可检测的探针引入细胞（如图1B所示）。我们之前已经证明n -左旋丙烯酰甘露胺（ManLev, 1a, Scheme 1）被细胞代谢成n -左旋丙烯酰唾液酸（SiaLev）（2a），然后附加到糖缀合物上，最终在细胞表面表达。[3,8]增加1a的n -酰基侧链的长度或空间体积可以消除细胞
Novel chemical reactivity can be introduced onto cell surfaces through metabolic oligosaccharide engineering.[1, 2] This technique exploits the substrate promiscuity of cellular biosynthetic enzymes to deliver unnatural monosaccharides bearing bioorthogonal functional groups into cellular glycans. For example, derivatives of N-acetylmannosamine (ManNAc) are converted by the cellular biosynthetic machinery into the corresponding sialic acids and subsequently delivered to the cell surface in the form of sialoglycoconjugates (Figure 1A). Analogs of N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) are also metabolized and incorporated into cell surface glycans, likely through the sialic acid and GalNAc salvage pathways, respectively.[3-6] Furthermore, GlcNAc analogs can be incorporated into nucleocytoplasmic proteins in place of β-O-GlcNAc residues.[7] These pathways have been exploited to integrate unique electrophiles such as ketones and azides into the target glycoconjugate class. These functional groups can be further elaborated in a chemoselective fashion by condensation with hydrazides [8] and by Staudinger ligation [9], respectively, thereby introducing detectable probes onto the cell (shown schematically in Figure 1B).We have previously demonstrated that N-levulinoylmannosamine (ManLev, 1a, Scheme 1) is metabolized by cells to N-levulinoyl sialic acid (SiaLev)(2a), which is then appended to glycoconjugates that are ultimately expressed on the cell surface.[3, 8] Increasing the length or steric bulk of the N-acyl side chain of 1a abrogates cell