Biosynthesis and Enzymology of Antifungal Natural Products

抗真菌天然产物的生物合成和酶学

• 批准号: 10291416
• 负责人: NEIL K GARG
• 金额: $ 51.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-15 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291416
• 关键词: 2-hydroxypyridine; Acids; Address; Alder plant; Alkaloids; Amphotericin; Anabolism; Antifungal Agents; Antifungal Therapy; Azole resistance; Biochemical; Biochemical Reaction; Biological; Biological Models; Catalysis; Chemistry; Comparative Study; Complex; Computing Methodologies; Crystallization; Cyclization; Cyclohexanes; Cytochrome P450; Drug resistance; Electrons; Engineering; Enzymatic Biochemistry; Enzymes; Family; Frequencies; Genome; Homologous Gene; Infection; Investigation; Knowledge; Methods; Mining; Natural Products; Nature; Outcome; Paper; Pathway interactions; Pharmaceutical Preparations; Play; Property; Reaction; Research; Role; S-Adenosylmethionine; Side; Specificity; Structure; Therapeutic; Tyrosine; Work; analog; computational chemistry; cycloaddition; decalin; drug discovery; improved; inhibitor; insight; interest; mortality; multidisciplinary; nanomolar; pathogenic fungus; prevent; resistance mechanism; respiratory; scaffold; weapons

ABSTRACT The combination of high frequencies of infection, high mortality rates, emergence of drug resistance, small number of therapeutic options and a depleted discovery pipeline has resulted in an urgent need for finding new antifungal molecules. Natural products, especially those produced by fungal species as natural antifungal weapons, have been and will continue to play important roles and provide leads for drug discovery. Realizing the immense potential of natural products as antifungal leads, and the prospects of discovering new structures through genome-guided methods, we are proposing a comprehensive and multidisciplinary project to investigate the biosynthesis of fungal-derived 2-pyridone alkaloids, which are complex natural products with potent and selective antifungal activities. We will be particularly focused on a diverse set of enzyme-catalyzed pericyclic reactions that give rise to the polycyclic scaffold important for biological activity. Uncovering these enzymes, followed by detailed investigation of the mechanisms and sequence-activity relationships, will improve our fundamental understanding of enzyme catalysis, and enable biosynthetic engineering approaches to generate natural product analogs, and expand genome mining leads for new antifungals. This multi-PI proposal bring together complementary expertise in three aspects of natural product research: biosynthesis, computational chemistry and synthesis. Together we will address three aims: 1) Investigate SAM-dependent pericyclase using leporin as a model system. 2) Investigate Alder-Ene and dephenylation reactions in pyridoxatin biosynthesis; and 3) Investigate biosynthesis of decalin-containing antifungal 2-pyridone compounds. Insights into the biosynthesis of these molecules will reveal fundamental insights into enzymes that catalyze pericyclic reactions, and provide leads for structure-guided natural product discovery.

抽象的 高频率感染，高死亡率，耐药性出现的结合， 少量的治疗选择和耗尽的发现管道导致迫切需要查找 新的抗真菌分子。天然产品，尤其是真菌物种作为天然抗真菌生产的产品 武器已经过去并且将继续扮演重要角色，并为毒品发现提供潜在客户。实现 天然产物作为抗真菌铅的巨大潜力，以及发现新结构的前景 通过基因组引导的方法，我们提出了一个全面的多学科项目来调查 真菌衍生的2-吡啶酮生物碱的生物合成，它们是具有有效和有效和的复杂天然产物 选择性抗真菌活动。我们将特别专注于各种酶催化的周环。 引起对生物活性重要的多环状支架的反应。发现这些酶， 然后对机制和序列关系的详细研究将改善我们的 对酶催化的基本了解，并启用生物合成工程方法生成 天然产物类似物和扩展基因组采矿可用于新的抗真菌剂。这个多PI提案带来 在自然产品研究的三个方面共同互补的专业知识：生物合成，计算 化学和合成。我们将共同解决三个目标：1）使用使用SAM依赖性周环酶 Leporin作为模型系统。 2）研究吡ido蛋白生物合成中的al烯和去烯基化反应； 3）研究含十二氨酸脱氨酰抗真菌2-吡啶酮化合物的生物合成。洞悉 这些分子的生物合成将揭示对催化周环反应的酶的基本见解， 并为结构引导的自然产品发现提供潜在客户。