Investigating biosynthetic enzymes to enhance natural product discovery

研究生物合成酶以增强天然产物的发现

• 批准号: 10713321
• 负责人: Melanie Ann Higgins
• 金额: $ 36.14万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713321
• 关键词: Anabolism; Biochemical Reaction; Biological Availability; Complex; Enzymatic Biochemistry; Enzymes; Family; Gene Cluster; Genes; Genome; Health; Human; Lead; Link; Medicine; Methods; Mining; Modification; Natural Products; Pathway interactions; Play; Reaction; Research; Role; Structure; bioactive natural products; drug development; drug discovery; genetic information; glycosylation; glycosyltransferase; guided inquiry; hygromycin A; improved; novel; programs; scaffold; small molecule; tool

Project Summary Natural products (NPs) have diverse complex structures and play a vital role in drug discovery and development. Although the rate of discovery of natural products has increased significantly, traditional bioactivity-guided discovery methods frequently lead to the re-discovery of known compounds. Therefore, genetic information- driven isolation is becoming a powerful tool to uncover novel NPs. Genome mining efforts that target genes responsible for the biosynthesis of core structures of major NP classes, has identified tens of thousands of new biosynthetic gene cluster (BGC) families predicted to produce novel compounds. While this method has been very successful in predicting compounds from these major classes, it is limited to those scaffolds and cannot identify other specific features of NP structures. Furthermore, these methods will overlook “hidden” BGCs that do not contain traditional core biosynthetic machinery, leaving a major gap in NP discovery. The first direction of this proposal aims to use specialized genome mining strategies that target NP glycosyltransferases to identify uncharacterized BGCs that produce bioactive glycosylated NPs with distinct core structures. Consequently, identified compounds will be directly linked to their BGC and likely have biosynthetic pathways that consist of unique enzymes and biochemical reactions. The second direction of this proposal is to interrogate the activities and mechanisms of new biosynthetic enzymes. These will include enzymes discovered in direction one, along with enzymes responsible for the biosynthesis of the aminocyclitol found in hygromycin A, that contains a rare modification essential for bioavailability. Subsequent re-integration of newly characterized biosynthetic enzymes into standard or specialized genome mining methods will assist in annotating and identifying additional BGCs to improve NP discovery. In addition, these enzymes will add to the growing toolbox of biocatalytic reactions exploited for unnatural small molecule biosynthesis. Ultimately, this research program will significantly advance NP and enzymology research to boost drug discovery and development for the benefit of human health.

项目摘要 天然产品（NP）具有累积的复杂结构，并在药物发现和开发中起着至关重要的作用。 尽管天然产品的发现率显着增加，但传统生物活性引导 发现方法经常导致已知化合物的重新发现。因此，遗传信息 - 驱动的隔离正在成为发现新颖NP的强大工具。靶向基因的基因组采矿工作 负责主要NP类的核心结构的生物合成，已经确定了成千上万的新 生物合成基因簇（BGC）家族预测会产生新的化合物。虽然这种方法已经 非常成功地预测这些主要阶层的化合物，它仅限于这些脚手架，不能 确定NP结构的其他特定特征。此外，这些方法将忽略“隐藏” BGC 请勿包含传统的核心生物合成机械，而在NP发现中留下了主要差距。第一个方向 该建议旨在使用针对NP糖基转移酶的专业基因组挖掘策略来识别 产生具有不同核心结构的生物活性糖基化NP的未表征的BGC。最后， 已鉴定的化合物将直接链接到其BGC，并且可能具有由生物合成途径链接 独特的酶和生化反应。该提议的第二个方向是审问活动 和新生物合成酶的机制。这些将包括沿方向发现的酶 用负责在湿霉素A中发现的氨基辛醇的生物合成的酶，其中含有罕见的 修改生物利用度必不可少的。随后的新特征生物合成酶的重新融合 进入标准或专业的基因组挖掘方法将有助于注释和识别其他BGC 改善NP发现。此外，这些酶将添加到生长的生物催化反应工具箱中 利用不自然的小分子生物合成。最终，该研究计划将大大发展 NP和酶学研究以增强药物发现和开发，以造福人类健康。