Studies of naturally occurring structurally modified carbohydrates

天然结构修饰碳水化合物的研究

• 批准号: 7752560
• 负责人: Xi Chen
• 金额: $ 27.26万
• 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/7752560
• 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; Oligosaccharides; Pasteurella multocida; Pathologic Processes; Phosphorylation; Physical condensation; Physiological; Physiology; Pituitary Hormones; Play; Positioning Attribute; Process; Protein-Carbohydrate Interaction; Proteins; Proteoglycan; Pyruvate; Pyruvates; 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

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.

碳水化合物的结构修饰是自然界中普遍存在的现象。例如，硫酸盐化 一些蛋白多糖、糖蛋白和糖脂中的碳水化合物被认为起了作用。 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，如硫酸盐化、磷酸化、甲基化、乙酰化和乳糖化，会导致 观察到自然界中50多种不同的唾液酸形态。然而，人们对香港特别行政区知之甚少 (结构-活性关系)由于获得这些碳水化合物修饰的技术困难 均相结构修饰的碳水化合物和糖共轭化合物。这项计划的长期目标是 开发化学-酶法合成天然碳水化合物 目的是为了更好地了解它们的生物学作用。在当前授予中 在此期间，我们将重点研究含唾液酸的结构。 唾液酸是一类带负电荷的9碳糖，主要被发现为 脊椎动物糖结合物中最外层的碳水化合物。因为其他人遇到的前线 生物分子、唾液酸在多种生理和病理过程中起着关键作用，包括 细胞-细胞相互作用、信号、炎症和感染等。基于唾液酸的识别过程 据信与唾液酸的精细结构密切相关，这种碳水化合物结构与唾液酸密切相关 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 包含大多数这些自然产生的不同结构的唾液酸苷文库，并将其应用于 蛋白质-碳水化合物相互作用研究。这项提议的具体目的是：1.化学合成 不同的唾液酸类似物及其前体；2.酶法合成CMP-唾液酸衍生物和 用唾液酸法研究获得的唾液酸苷文库的构效关系 酸识别蛋白质。因为唾液酸是许多生理和病理过程中的关键元素 进程，完成拟议的研究也可能有助于发现和开发新的 治疗人类疾病，如癌症、炎症性疾病、传染性疾病和其他致病性疾病。

项目成果

Chemoenzymatic synthesis of GD3 oligosaccharides and other disialyl glycans containing natural and non-natural sialic acids.

GD3寡糖和其他含有天然和非天然唾液酸的混合物的化学酶合成。

• DOI: 10.1021/ja907750r
• 发表时间: 2009-12-30
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Yu, Hai;Cheng, Jiansong;Ding, Li;Khedri, Zahra;Chen, Yi;Chin, Sharlene;Lau, Kam;Tiwari, Vinod Kumar;Chen, Xi
• 通讯作者: Chen, Xi

Recent progress in chemical and chemoenzymatic synthesis of carbohydrates.

• DOI: 10.1016/j.cbpa.2009.09.013
• 发表时间: 2009-12
• 期刊: CURRENT OPINION IN CHEMICAL BIOLOGY
• 影响因子: 7.8
• 作者: Muthana, Saddam;Cao, Hongzhi;Chen, Xi
• 通讯作者: Chen, Xi

Parallel chemoenzymatic synthesis of sialosides containing a C5-diversified sialic acid.

• DOI: 10.1016/j.bmcl.2009.08.078
• 发表时间: 2009-10-15
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Cao H;Muthana S;Li Y;Cheng J;Chen X
• 通讯作者: Chen X

Combinatorial chemoenzymatic synthesis and high-throughput screening of sialosides.

组合化学酶合成和唾液酸的高通量筛选。

• DOI: 10.1021/cb800127n
• 发表时间: 2008-09-19
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Chokhawala, Harshal A.;Huang, Shengshu;Lau, Kam;Yu, Hai;Cheng, Jiansong;Thon, Vireak;Hurtado-Ziola, Nancy;Guerrero, Juan A.;Varki, Ajit;Chen, Xi
• 通讯作者: Chen, Xi

High-throughput neuraminidase substrate specificity study of human and avian influenza A viruses.

• DOI: 10.1016/j.virol.2011.03.024
• 发表时间: 2011-06-20
• 期刊: Virology
• 影响因子: 3.7
• 作者: Li Y;Cao H;Dao N;Luo Z;Yu H;Chen Y;Xing Z;Baumgarth N;Cardona C;Chen X
• 通讯作者: Chen X