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 天然产物具有复杂多样的结构，在药物发现和开发中发挥着重要作用。 尽管天然产物的发现率显著提高，但传统的生物活性导向 发现方法经常导致已知化合物的重新发现。因此，遗传信息- 驱动隔离正成为发现新颖NP的有力工具。针对基因的基因组挖掘工作 负责主要NP类核心结构的生物合成，已经鉴定了数万种新的 生物合成基因簇（BGC）家族预测产生新的化合物。虽然这种方法已经 它在预测这些主要类别的化合物方面非常成功，但它仅限于这些支架， 识别NP结构的其他具体特征。此外，这些方法将忽略“隐藏的”BGC， 不包含传统的核心生物合成机制，在NP发现中留下了重大空白。的第一方向 该提案旨在使用专门的基因组挖掘策略，以NP糖基转移酶为目标， 未表征的BGC产生具有不同核心结构的生物活性糖基化NP。因此，委员会认为， 已鉴定的化合物将直接与其BGC相关，并且可能具有生物合成途径， 独特的酶和生化反应。这项建议的第二个方向是询问活动 和新的生物合成酶的机制。这些将包括在方向一发现的酶，沿着 与潮霉素A中发现的负责氨基环醇生物合成的酶，含有罕见的 对生物利用度至关重要的修饰。随后重新整合新表征的生物合成酶 标准或专门的基因组挖掘方法将有助于注释和识别额外的BGC， 改进NP发现。此外，这些酶将增加到不断增长的生物催化反应的工具箱 用于非天然小分子生物合成。最终，这项研究计划将大大推进 NP和酶学研究促进药物发现和开发，造福人类健康。