Keppler O T, Horstkorte R, Pawlita M, Schmidt C, Reutter W
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany.
Glycobiology. 2001 Feb;11(2):11R-18R. doi: 10.1093/glycob/11.2.11r.
N-Acetylneuraminic acid is the most prominent sialic acid in eukaryotes. The structural diversity of sialic acid is exploited by viruses, bacteria, and toxins and by the sialoglycoproteins and sialoglycolipids involved in cell-cell recognition in their highly specific recognition and binding to cellular receptors. The physiological precursor of all sialic acids is N-acetyl D-mannosamine (ManNAc). By recent findings it could be shown that synthetic N-acyl-modified D-mannosamines can be taken up by cells and efficiently metabolized to the respective N-acyl-modified neuraminic acids in vitro and in vivo. Successfully employed D-mannosamines with modified N-acyl side chains include N-propanoyl- (ManNProp), N-butanoyl- (ManNBut)-, N-pentanoyl- (ManNPent), N-hexanoyl- (ManNHex), N-crotonoyl- (ManNCrot), N-levulinoyl- (ManNLev), N-glycolyl- (ManNGc), and N-azidoacetyl D-mannosamine (ManNAc-azido). All of these compounds are metabolized by the promiscuous sialic acid biosynthetic pathway and are incorporated into cell surface sialoglycoconjugates replacing in a cell type-specific manner 10-85% of normal sialic acids. Application of these compounds to different biological systems has revealed important and unexpected functions of the N-acyl side chain of sialic acids, including its crucial role for the interaction of different viruses with their sialylated host cell receptors. Also, treatment with ManNProp, which contains only one additional methylene group compared to the physiological precursor ManNAc, induced proliferation of astrocytes, microglia, and peripheral T-lymphocytes. Unique, chemically reactive ketone and azido groups can be introduced biosynthetically into cell surface sialoglycans using N-acyl-modified sialic acid precursors, a process offering a variety of applications including the generation of artificial cellular receptors for viral gene delivery. This group of novel sialic acid precursors enabled studies on sialic acid modifications on the surface of living cells and has improved our understanding of carbohydrate receptors in their native environment. The biochemical engineering of the side chain of sialic acid offers new tools to study its biological relevance and to exploit it as a tag for therapeutic and diagnostic applications.
N-乙酰神经氨酸是真核生物中最主要的唾液酸。病毒、细菌、毒素以及参与细胞间识别的唾液酸糖蛋白和唾液酸糖脂利用唾液酸的结构多样性，实现对细胞受体的高度特异性识别和结合。所有唾液酸的生理前体是N-乙酰-D-甘露糖胺（ManNAc）。最近的研究发现表明，合成的N-酰基修饰的D-甘露糖胺能够被细胞摄取，并在体外和体内有效地代谢为相应的N-酰基修饰的神经氨酸。成功应用的具有修饰N-酰基侧链的D-甘露糖胺包括N-丙酰基-（ManNProp）、N-丁酰基-（ManNBut）-、N-戊酰基-（ManNPent）、N-己酰基-（ManNHex）、N-巴豆酰基-（ManNCrot）、N-乙酰丙酰基-（ManNLev）、N-糖基-（ManNGc）以及N-叠氮乙酰-D-甘露糖胺（ManNAc-叠氮）。所有这些化合物都通过混杂的唾液酸生物合成途径进行代谢，并以细胞类型特异性的方式掺入细胞表面唾液酸糖缀合物中，取代10 - 85%的正常唾液酸。将这些化合物应用于不同的生物系统，揭示了唾液酸N-酰基侧链的重要且意想不到的功能，包括其在不同病毒与其唾液酸化宿主细胞受体相互作用中的关键作用。此外，用ManNProp处理（与生理前体ManNAc相比仅多一个亚甲基）可诱导星形胶质细胞、小胶质细胞和外周T淋巴细胞的增殖。利用N-酰基修饰的唾液酸前体，可以将独特的、具有化学反应性的酮基和叠氮基生物合成地引入细胞表面唾液酸聚糖中，这一过程具有多种应用，包括生成用于病毒基因递送的人工细胞受体。这组新型唾液酸前体使得对活细胞表面唾液酸修饰的研究成为可能，并增进了我们对天然环境中碳水化合物受体的理解。唾液酸侧链的生化工程提供了新的工具，用于研究其生物学相关性，并将其作为治疗和诊断应用的标记加以利用。
