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Biosynthesis and Enzymology of Antifungal Natural Products

抗真菌天然产物的生物合成和酶学

基本信息

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
项目类别：
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

项目摘要

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.

摘要