Studies of naturally occurring structurally modified carbohydrates

天然结构修饰碳水化合物的研究

• 批准号: 7164411
• 负责人: Xi Chen
• 金额: $ 27.18万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7164411
• 关键词: Acetylation; Acylneuraminate Cytidylyltransferase; Anabolism; Animals; Binding; Binding Proteins; Biochemical; Biological; Biological Process; Carbohydrates; Carbon; Cell Communication; Cells; Charge; Chemicals; Cytidine Monophosphate N-Acetylneuraminic Acid; Degradation Pathway; Development; Disease; Enzymes; Epitopes; Escherichia coli; Family; Glycoconjugates; Glycolipids; Glycoproteins; Glycosaminoglycans; Goals; Grant; Hemagglutinin; Heparin; Human; Indium; Infection; Inflammation; Inflammatory; Inorganic Sulfates; Keratin; Lactams; Lactones; Lead; Libraries; Ligands; Link; Malignant Neoplasms; Mannose; Membrane Glycoproteins; Methods; Methylation; Modification; Monosaccharides; N-Acetylneuraminate lyase; Nature; Neuraminidase; Numbers; Oligosaccharides; Pasteurella multocida; Pathologic Processes; Phosphorylation; Physical condensation; Physiological; Physiology; Pituitary Hormones; Play; Positioning Attribute; Process; Protein-Carbohydrate Interaction; Proteins; Proteoglycan; Pyruvate; Pyruvates; Range; Reaction; Research; Research Personnel; Role; Selectins; Sialic Acids; Sialyltransferases; Signal Transduction; Source; Structure; Structure-Activity Relationship; Substrate Specificity; Sulfoglycosphingolipids; System; Unspecified or Sulfate Ion Sulfates; Vertebrates; Viral; Virus; analog; analytical method; base; carbohydrate structure; chemical synthesis; dermatan sulfate chondroitin sulfate; human disease; microorganism; molecular recognition; novel; novel therapeutics; pathogenic bacteria; programs; seminolipid; sugar; sulfation

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：碳水化合物的结构修饰是自然界中的常见现象。例如，存在于许多蛋白聚糖、糖蛋白和糖脂中的硫酸化碳水化合物被认为在特定的分子识别过程中起重要作用。此外，唾液酸单糖的修饰，如硫酸化、磷酸化、甲基化、乙酰化和乳酸化，导致在自然界中观察到50多种不同的唾液酸形式。然而，鲜为人知的是，这些碳水化合物修饰的SAR（结构-活性关系），由于在获得均匀的结构修饰的碳水化合物和糖缀合物的技术困难。该计划的长期目标是开发新的化学-酶促方法，用于合成具有天然修饰的结构确定的碳水化合物，并更好地了解其生物学作用。在当前的资助期内，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，其主要被发现作为脊椎动物糖缀合物的最外层碳水化合物。唾液酸作为其他生物分子的前线，在细胞间相互作用、信号传导、炎症和感染等多种生理和病理过程中发挥着重要作用。唾液酸的识别过程与唾液酸的精细结构、与唾液酸连接的糖结构以及它们之间的连接方式密切相关。我们建议化学-酶法合成一个唾液酸苷库，其中包含大多数这些天然存在的不同结构，并将其应用于蛋白质-碳水化合物相互作用的研究。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-唾液酸衍生物和唾液酸苷文库; 3.利用唾液酸识别蛋白研究所获得的唾液酸苷库的构效关系（SAR）。由于唾液酸是许多生理和病理过程中的关键元素，因此完成所提出的研究还可以促进发现和开发用于人类疾病如癌症、炎症、传染病和其他病原性疾病的新疗法。