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(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。这些糖作为许多具有生物活性的天然产物的有效性和特异性的关键成分的建立表明，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母体分子的生理特性。充分实现这种方法的潜力需要彻底了解每个目标糖的生物合成途径，包括遗传、酶和机制信息。通过这笔赠款资助的我们的工作，为实现这些目标所作的努力取得了一些显著成果。在上一次资助期间，我们研究了具有代表性的支链糖--麦芽糖、耶西尼糖和半乳呋喃糖，以及两种氨基糖--麦芽糖和脱糖胺的形成。我们还扩大了这个项目的范围，探索了通过操纵糖生物合成设备来改变大环内酯类抗生素中添加的糖来产生新的糖结合物的可行性。根据这些研究，我们现已确定了三个值得在下一批资助期内进一步深入研究的范畴。我们的计划是(A)研究TDP-二氢链糖合成酶催化二氢单糖的形成机理，(B)研究一种特殊的硝化糖--猕猴桃糖的生物合成，以及(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猕猴桃糖生物合成的整个途径，并表征涉及二氢链糖和猕猴桃糖形成的C-C和C-N键形成步骤的机制。这些研究不仅将有助于描述负责的酶是如何影响化学转化的，而且还将有助于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洞察力将允许通过将所需的糖与由适当的糖基转移酶催化的各种糖苷元偶联来合理设计杂交糖偶联物，利用这两个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带来了希望，这些新的化学实体最终将被用于对抗对人类健康的无数微生物威胁。总体而言，我们的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。