Studies of naturally occurring structurally modified carbohydrates

碳水化合物的结构修饰是自然界中普遍存在的现象。例如，硫酸盐 许多蛋白聚糖、糖蛋白和糖脂中的碳水化合物被认为起着 在特定的分子识别过程中发挥重要作用。此外，唾液酸的修饰 单糖，如硫酸化、磷酸化、甲基化、乙酰化和乳酰化，导致 在自然界中观察到超过50种不同的唾液酸形式。然而，人们对特区知之甚少 由于获得这些碳水化合物修饰的技术困难， 均质结构修饰的碳水化合物和糖缀合物。该计划的长期目标是 开发新的化学-酶法合成结构确定的碳水化合物， 发生的修饰，并提供更好地了解其生物学作用。在目前的授予 在此期间，我们将集中精力研究含唾液酸的结构。 唾液酸是一个带负电荷的9碳糖家族，主要被发现为 脊椎动物糖复合物最外层的碳水化合物。当其他人遇到的前线 唾液酸作为一种生物分子，在多种生理和病理过程中发挥着关键作用，包括 细胞间相互作用、信号传导、炎症和感染等。 被认为与唾液酸的精细结构密切相关， 唾液酸，以及它们之间的连接类型。我们建议用化学酶法合成 含有这些天然存在的多种结构中的大多数的唾液酸苷文库，并将其应用于 蛋白质-碳水化合物相互作用研究。该提案的具体目标是：1.化学合成 多种唾液酸类似物及其前体; 2.酶促合成CMP-唾液酸衍生物， 唾液酸苷文库; 3.利用唾液酸对所获得的唾液酸苷库进行构效关系（SAR）研究 酸识别蛋白。由于唾液酸是许多生理和病理过程中的关键元素， 完成拟议的研究也可能有助于发现和开发新的 用于人类疾病如癌症、炎性疾病、感染性疾病和其它病原性疾病的治疗剂。

Structural modification of carbohydrates is a common phenomenon in nature. For example, sulfated carbohydrates presented in a number of proteoglycans, glycoproteins, and glycolipids are believed to play important roles in specific molecular recognition processes. Furthermore, modifications of sialic acid monosaccharides, such as sulfation, phosphorylation, methylation, acetylation, and lactylation, lead to the observation of more than 50 different sialic acid forms in nature. Little is known, however, about the SAR (structure-activity relationship) of these carbohydrate modifications due to technical difficulties in obtaining homogenous structurally modified carbohydrates and glycoconjugates. The long-term goal of this program is to develop novel chemo-enzymatic methods for synthesizing structurally defined carbohydrates with naturally occurring modifications and to provide better understanding of their biological roles. In the current granting period, we will focus our efforts on the sialic acid-containing structures. Sialic acids are a family of negatively charged 9-carbon sugars that have been predominantly found as the outermost carbohydrates of vertebrate glycoconjugates. As the frontline encountered by other biomolecules, sialic acids play pivotal roles in a variety of physiological and pathological processes, including cell-cell interaction, signaling, inflammation, and infection etc. The sialic acid-based recognition processes are believed to be closely related to the fine structures of the sialic acids, the carbohydrate structures linked to the sialic acids, and the types of the linkages in between. We propose to chemo-enzymatically synthesize a sialoside library containing the majority of these naturally occurring diverse structures and apply it in protein-carbohydrate interaction studies. The specific aims of the proposal are to: 1. chemically synthesize diverse sialic acid analogs and their precursors; 2. enzymatically synthesize CMP-sialic acid derivatives and a sialoside library; 3. study structure-activity relationship (SAR) of the obtained sialoside library using sialic acid-recognizing proteins. As sialic acids are key elements in many physiological and pathological processes, accomplishing the proposed studies may also facilitate the discovery and development of new therapeutics for human diseases such as cancer, inflammatory, infectious, and other pathogenic diseases.