Mechanistic Studies of Deoxy Sugar Biosynthesis

脱氧糖生物合成的机理研究

基本信息

批准号：
8851606
负责人：
HUNG-WEN LIU
金额：
$ 36.96万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-01-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851606
关键词：
Address Anabolism Anti-Bacterial Agents Antibiotics Antiviral Agents Area Attention Biochemistry Biological Biological Factors Biomedical Research Biotechnology Carbohydrates Carbon Catalysis Characteristics Chemicals Chemistry Cobalamin Complement Complex Deaminase Deamination Dehydration Deoxy Sugars Development Drug Design Drug Industry Engineering Enzymatic Biochemistry Enzymes Ethanolamine Ammonia-Lyase Foundations Funding Future Generations Genetic Gentamicins Glucose Goals Grant Health Investigation Lead Learning Lyase Mediating Metabolism Methods Methylation Methyltransferase Nature Outcome Oxidoreductase Parents Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Physiological Play Production Property Reaction Reporting Research Ribose Role Structure Sulfur System Tobramycin Work antimicrobial appendage base carbohydrate biosynthesis combinatorial comparative dehydrogenation desosamine drug development drug discovery enzyme pathway human disease in vivo insight interest member novel oxetane programs research and development research study success sugar thiosugar

项目摘要

DESCRIPTION (provided by applicant): A great majority of compounds important for the treatment and study of human disease have their origin in natural products. These compounds are frequently modified with carbohydrate appendages that are critical for their biological activities and, in many cases, modulate their medicinal properties. It therefore comes as no surprise that these carbohydrates demonstrate an incredible range of structural variability, despite their origin in only a handful of precursors from primary metabolism. By exploiting the biosynthetic machinery of these unusual sugars it is possible to enhance or vary the physiological characteristics of the parent molecules and apply the principles learned to new systems. However, in order to fully realize the potential of such an approach, the biosynthetic pathways of these sugars must be characterized and the underlying chemistry thoroughly understood at the mechanistic level. In this spirit, our previous efforts funded by this grant have yielded many notable and important contributions to the goal of providing a scientific foundation for pharmaceutical research and potential drug development. As a result of these studies, we have identified three key areas that warrant further investigation in the next grant period. Accordingly, this proposal outlines experiments targeting the biosynthetic pathways and enzymes for the production of methylthiolincosamide, desosamine, tobramycin, oxetanocin, and the carbohydrate appendages of gentamicin. The specific objectives include: (1) study of the fundamental principles by which organic radicals are controlled to effect deamination, dehydrogenation and dehydration reactions catalyzed by the radical SAM enzymes DesII and AprD4, (2) pioneering mechanistic investigations into the B12-dependent radical SAM enzymes responsible for C- methylation reaction catalyzed by GenK and the ribose-to-oxetane ring-contraction catalyzed by OxsB, and (3) elucidation of the biosynthetic mechanism of sulfur incorporation into methylthiolincosamide. The enzymes OxsB and GenK are of particular interest because they are members of an emerging class of cobalamin- dependent radical SAM enzymes about which virtually nothing is presently known. These research directions are identified on the basis of their novelty, implications for the field of mechanistic enzymology, and potential utility in biomedical research at the basic and translational levels. We believe this wor will continue to address standing questions in biological chemistry and open new avenues of discovery in secondary metabolism and pharmaceutical research.

描述（由申请人提供）：绝大多数对人类疾病的治疗和研究很重要的化合物都源自天然产物。这些化合物经常用碳水化合物附加物进行修饰，这些附加物对其生物活性至关重要，并且在许多情况下还可以调节其药用特性。因此，毫不奇怪，这些碳水化合物表现出令人难以置信的结构变异性，尽管它们仅起源于初级代谢的少数前体。通过利用这些不寻常糖的生物合成机制，可以增强或改变母体分子的生理特征，并将学到的原理应用于新系统。然而，为了充分发挥这种方法的潜力，必须对这些糖的生物合成途径进行表征，并在机械水平上彻底了解其潜在的化学性质。本着这种精神，我们之前由这笔赠款资助的努力已经为药物研究和潜在药物开发提供科学基础的目标做出了许多显着且重要的贡献。根据这些研究的结果，我们确定了三个关键领域，需要在下一个资助期内进一步研究。因此，该提案概述了针对生产甲硫基林考酰胺、去糖胺、妥布霉素、氧杂星和庆大霉素碳水化合物附属物的生物合成途径和酶的实验。具体目标包括：（1）研究控制有机自由基以实现自由基 SAM 酶 DesII 和 AprD4 催化的脱氨、脱氢和脱水反应的基本原理，（2）对 B12 依赖的自由基 SAM 进行开创性的机制研究负责由 GenK 催化的 C-甲基化反应和由OxsB，以及(3)阐明硫掺入甲硫基林可酰胺的生物合成机制。 OxsB 和 GenK 酶特别令人感兴趣，因为它们是一类新兴的钴胺素依赖性自由基 SAM 酶的成员，目前对此几乎一无所知。这些研究方向是根据其新颖性、对机械酶学领域的影响以及在基础和转化层面的生物医学研究中的潜在效用。我们相信这项工作将继续解决生物化学中的长期问题，并为次级代谢和药物研究开辟新的发现途径。