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（由申请人提供）：碳水化合物的结构修饰本质上是一种常见现象。例如，在许多蛋白聚糖，糖蛋白和糖脂中呈现的硫化碳水化合物被认为在特定的分子识别过程中起着重要作用。此外，唾液酸单糖的修饰，例如硫酸化，磷酸化，甲基化，乙酰化和乳酸化，导致观察到自然界中50多种不同的唾液酸形成。然而，由于技术困难在获得结构修饰的碳水化合物和糖缀合物方面的技术困难，这些碳水化合物修饰的SAR（结构活性关系）知之甚少。该程序的长期目标是开发新型的化学酶方法，用于合成具有自然发生的修饰的结构定义的碳水化合物，并更好地了解其生物学作用。在当前的授予期内，我们将把精力集中在含唾液酸的结构上。 唾液酸是一个带负电荷的9碳糖的家族，主要是脊椎动物糖缀合物的最外层碳水化合物。 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.我们建议从化学酶合成一个包含这些天然存在的多种结构的大多数的唾液酸库文库，并将其应用于蛋白质 - 碳水化合物相互作用研究中。该提案的具体目的是：1。化学合成各种唾液酸类似物及其前体； 2。酶合成CMP-Sialic酸衍生物和唾液酸库库； 3。使用唾液酸识别蛋白获得的唾液酸库的研究结构活性关系（SAR）。由于唾液酸是许多生理和病理过程中的关键因素，因此完成拟议的研究也可能促进和开发针对人类疾病的新疗法，例如癌症，炎症，感染性和其他病原性疾病。