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

C-C

• 批准号: 6783862
• 负责人: HUNG-WEN LIU
• 金额: $ 32.42万
• 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/6783862
• 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）：分支链糖和含氮糖是两种重要的天然碳水化合物。将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成部分的建立，据称通过利用其生物合成机器来改变和/或交换这些关键糖结构的想法可以增强或改变其父母分子的生理特征。充分意识到这种方法的潜力需要对每个目标糖的生物合成途径进行透彻的了解，包括遗传，酶促和机械信息。针对这些目标的努力通过这笔赠款资助的我们的工作取得了一些显着的结果。在最后一个赠款期间，我们研究了代表性的分支链糖的形成 - 霉菌，Yersiniose和calactofuranose，以及两种氨基糖 - 霉菌糖和丙想胺。我们还通过探索通过操纵糖的生物合成机器来改变大花环抗生素中的糖的可行性来扩大该项目的范围。由于这些研究，我们现在已经确定了在下一个赠款期间值得进一步深入调查的三个领域。该提案中概述的是我们的计划（a）研究由TDP-二氢诱发合酶催化二氢螺旋藻的机制，（b）研究了一种不寻常的硝基果糖，kijanose，kijanose和（c）的生物合成，以利用催化能力的催化能力。生物合成应用中的糖基转移酶。前两个项目的预期目标是建立kijanose生物合成的整个途径，并表征C-C和C-N键形成步骤的机制，涉及形成二氢蛋白酶和kijanose。这些研究不仅将有助于描述负责任酶如何影响化学转化，而且还将促进未来的治疗设计工作，以控制和/或模仿其催化作用。从第三个项目中获得的洞察力将允许通过与适当的糖基转移酶催化的各种含糖的所需糖偶联来合理设计杂化糖缀合物，从而促进了两个组件提供的结构多样性。这种组合方法对探索新化学实体的探索有望最终用来与无数的微生物威胁对人类健康作斗争。总体而言，我们的结果有望为酶化学的基本面做出重大贡献，并可能影响药物生物技术。