C-C & C-N Bond Formation in Unusual Sugar Biosynthesis

C-C

• 批准号: 6876066
• 负责人: HUNG-WEN LIU
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876066
• 关键词: Actinomycetales; aminosugar; carbohydrate biosynthesis; carbohydrate structure; chemical bond; enzyme mechanism; enzyme structure; enzyme substrate; expression cloning; glucosamine; hexoses; microorganism metabolism; monosaccharides; pentoses

DESCRIPTION (provided by applicant): Branched-chain sugars and nitrogen-containing sugars are two important classes of naturally occurring carbohydrates. The establishment of these sugars as vital components for the efficacy and specificity of many biologically active natural products has purported the idea that altering and/or exchanging these crucial sugar structures by exploiting their biosynthetic machineries may enhance or vary the physiological characteristics of their parent molecules. Fully realizing the potential of such an approach requires a thorough understanding of the biosynthetic pathway of each target sugar, including genetic, enzymatic, and mechanistic information. Efforts directed toward these goals have achieved some notable results through our work funded by this grant. In the last grant period, we studied the formation of representative branched-chain sugars -- mycarose, yersiniose and galactofuranose, and two amino sugars -- mycaminose, and desosamine. We also extended the scope of this project by exploring the feasibility of generating new glycoconjugates by manipulating the sugar biosynthetic machineries to alter the appended sugars in macrolide antibiotics. As a result of these studies, we have now identified three areas worthy of further in-depth investigation in the next grant period. Outlined in this proposal are our plans (A) to study the mechanism of the formation of dihydrosteptose catalyzed by TDP-dihydrostreptose synthase, (B) to investigate the biosynthesis of an unusual nitrosugar, kijanose, and (C) to exploit the catalytic capabilities of glycosyltransferases in biosynthetic applications. The intended goals of the first two projects are to establish the entire pathway for the biosynthesis of kijanose and to characterize the mechanisms of the C-C and C-N bond formation steps involved the formation of dihydrostreptose and kijanose. These studies will not only aid in delineating how chemical transformations are affected by the responsible enzymes, but will also facilitate future therapeutic design efforts to control and/or mimic their catalytic roles. The insight gained from the third project will allow rational design of hybrid glycoconjugates through the coupling of desired sugars with various aglycons catalyzed by the appropriate glycosyltransferases, harnessing the structural diversity provided by both components. Such a combinatorial approach holds promise for the exploration of new chemical entities that will ultimately be used to battle innumerable microbial threats to human health. Overall, our results are expected to make a significant contribution to the fundamentals of enzyme chemistry and possibly impact pharmaceutical biotechnology.

描述（由申请人提供）：支链糖和含氮糖是两类重要的天然碳水化合物。这些糖作为许多生物活性天然产物的功效和特异性的重要组分的确立已经提出了这样的想法，即通过利用它们的生物合成机制来改变和/或交换这些关键的糖结构可以增强或改变它们的亲本分子的生理特征。充分实现这种方法的潜力需要彻底了解每种目标糖的生物合成途径，包括遗传，酶和机械信息。通过这项赠款资助的工作，朝着这些目标的努力取得了一些显着的成果。在上一个资助期，我们研究了代表性支链糖的形成--真菌糖、耶尔森糖和呋喃半乳糖，以及两种氨基糖--真菌胺糖和desosamine。我们还通过探索通过操纵糖生物合成机制来改变大环内酯类抗生素中的附加糖来产生新的糖缀合物的可行性来扩展该项目的范围。经过这些研究，我们现确定了三个值得在下一个资助期内进一步深入研究的范畴。在这个计划中概述了我们的计划（A）研究由TDP-二氢链霉糖合酶催化的二氢链霉糖形成的机制，（B）研究一种不寻常的亚硝基糖--kijanose的生物合成，和（C）开发糖基转移酶在生物合成应用中的催化能力。前两个项目的预期目标是建立整个kijanose生物合成途径，并表征涉及形成二氢链霉菌糖和kijanose的C-C和C-N键形成步骤的机制。这些研究不仅有助于描述化学转化如何受到负责酶的影响，而且还将促进未来的治疗设计工作，以控制和/或模拟其催化作用。从第三个项目中获得的见解将允许通过适当的糖基转移酶催化的所需糖与各种糖苷配基的偶联来合理设计混合糖缀合物，利用两种组分提供的结构多样性。这种组合方法为探索新的化学实体提供了希望，这些化学实体最终将用于对抗对人类健康的无数微生物威胁。总的来说，我们的研究结果有望对酶化学的基础做出重大贡献，并可能影响制药生物技术。