DEOXYHEXOSE BIOSYNTHESIS

脱氧己糖生物合成

• 批准号: 6387080
• 负责人: HEINZ G FLOSS
• 金额: $ 26.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6387080
• 关键词: aminoglycoside antibiotics; biological products; carbohydrate analog; carbohydrate biosynthesis; enzyme reconstitution; glycosides; hexoses; microorganism metabolism; sugar nucleotide

Many of the naturally occurring antibiotics and other biologically active microbial metabolites are glycosides, representing a combination of one of a large number of different aglycones with one or more of a number of unusual sugars, particularly deoxy- and deoxyaminohexoses. The sugar component in these compounds is usually absolutely essential for biological activity. Most of these sugar moieties are synthesized from D- glucose at the level of a dTDP-hexose and then transferred to the aglycone by a glycosyltransferase. Yet, except for the very initial steps, our knowledge of the mechanisms and enzymes involved in these sugar nucleotide transformations is limited. This limited knowledge has been an impediment to an attractive application in drug discovery, the combinatorial biosynthesis of unnatural assemblies of the same sugars and aglycones. In the proposed project we plan to enhance our understanding of the formation of key deoxyhexose components of antibiotics by reconstituting, with recombinant enzymes expressed from the appropriate cloned antibiotic biosynthesis genes, the enzymatic formation of sugar nucleotides representing dTDP-2-deoxy-, 2,3- dideoxy-, 2,3-dideoxy-3-amino-, and 3,4-dideoxy-3-aminohexoses and by studying the mechanisms of their formation. This work will lay one of the foundations for the combinatorial enzymatic synthesis of new, unnatural glycosides representing new combinations of antibiotic sugars and aglycones.

许多天然存在的抗生素和其他具有生物活性的微生物代谢产物是糖苷，代表了大量不同的苷元中的一种与一种或多种不寻常的糖的组合，特别是脱氧和脱氧氨基己糖。这些化合物中的糖成分通常对生物活性是绝对必需的。这些糖大部分是在dtdp -己糖水平上由D-葡萄糖合成的，然后通过糖基转移酶转移到苷元上。然而，除了最初的步骤，我们对这些糖核苷酸转化的机制和酶的了解是有限的。这种有限的知识已经成为药物发现中有吸引力的应用的障碍，即相同糖和苷元的非自然组装的组合生物合成。在本项目中，我们计划通过重组适当克隆的抗生素生物合成基因表达的酶，重组代表dtdp -2-脱氧-、2,3-二脱氧-、2,3-二脱氧-3-氨基-和3,4-二脱氧-3-氨基己糖的糖核苷酸的酶促形成，并研究它们的形成机制，从而提高我们对抗生素关键脱氧己糖成分形成的理解。这项工作将为组合酶合成新的非天然糖苷奠定基础，这些糖苷代表了抗生素糖和苷元的新组合。