Studies of naturally occurring structurally modified carbohydrates

天然结构修饰碳水化合物的研究

基本信息

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
项目类别：
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

项目摘要

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本质上是一种常见现象。例如，硫化据信以许多蛋白聚糖，糖蛋白和糖脂的含量发挥作用的碳水化合物在特定分子识别过程中的重要作用。此外，唾液酸的修饰单糖（例如硫酸化，磷酸化，甲基化，乙酰化和乳酸化）导致在自然界观察50多种不同的唾液酸形式。然而，关于SAR的知之甚少由于获得技术困难而导致的这些碳水化合物修饰的（结构活性关系）同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型的化学酶方法，用于合成结构定义的碳水化合物发生修改并更好地了解其生物学作用。在当前授予中时期，我们将把精力集中在含唾液酸的结构上。唾液酸是一个负电荷的9碳糖的家族，主要被发现为脊椎动物糖缀合物的最外部碳水化合物。正如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关键作用，包括细胞 - 细胞相互作用，信号传导，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，碳水化合物结构相关到唾液酸，以及之间的连接类型。我们提出化学酶合成的化学合成包含大多数自然存在的多种结构的唾液膜库，并将其应用于蛋白质 - 碳水化合物相互作用研究。该提案的具体目的是：1。化学合成多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； 3。使用唾液的研究结构活性关系（SAR）酸识别的蛋白质。因为唾液酸是许多生理和病理学的关键元素过程，完成拟议的研究也可能有助于发现和发展新的癌症，炎症，传染性和其他致病性疾病等人类疾病的治疗剂。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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.

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.