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：
8729581
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729581
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 DNA Sequence Rearrangement 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 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 public health relevance 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）：绝大多数对于治疗和研究人类疾病重要的化合物起源于天然产物。这些化合物经常被碳水化合物附属物修饰，这些附属物对其生物活性至关重要，并且在许多情况下会调节其药用特性。因此，这些碳水化合物表现出令人难以置信的结构可变性，尽管它们起源于原代新陈代谢的少数前体，但毫不奇怪。通过利用这些异常糖的生物合成机制，可以增强或改变父分子的生理特征，并将学性学性的原理应用于新系统。但是，为了充分意识到这种方法的潜力，必须对这些糖的生物合成途径进行表征，并且在机械水平上彻底了解了基础化学。本着这种精神，我们以前由这笔赠款资助的努力为为药物研究和潜在药物开发提供科学基础的目标提供了许多值得注意的重要贡献。由于这些研究，我们确定了三个关键领域，这些领域需要在下一个赠款期间进行进一步调查。因此，该提案概述了针对生物合成途径和酶的实验，用于生产甲基硫醇糖胺，甲撒胺，毒素，氧甲霉素和庆大霉素的碳水化合物附属物。具体目标包括：（1）研究有机自由基的基本原理，以影响脱氨基，脱氢和脱水反应，由自由基Sam酶Desii和APRD4和APRD4催化，（2）先进的机械研究对B12依赖性的sam enzys contect contect contect contect contect contect contect contect contect contec：通过OXSB催化的环诱导，（3）阐明硫掺入甲基硫醇糖酰胺的生物合成机理。 OXSB和GENK酶特别有趣，因为它们是新兴的钴胺素依赖性的自由基SAM酶的成员，几乎没有什么知之甚少。这些研究方向是根据它们的新颖性，对机械酶学领域的影响以及基本和翻译水平生物医学研究的潜在效用。我们认为，这种问题将继续解决生物化学中的常规问题，并在二级代谢和制药研究中开放新的发现途径。