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Creating natural product diversity via the fabrication of a hybrid fatty acid-nonribosomal peptide synthetase

通过制造杂合脂肪酸-非核糖体肽合成酶创造天然产物多样性

基本信息

批准号：
10339399
负责人：
Joshua Catungal Corpuz
金额：
$ 1.99万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-04-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339399
关键词：
Achievement Address Amino Acids Anabolism Antibiotics Antifungal Agents Berry Biochemistry Biomedical Engineering Carrier Proteins Chemicals Clinic Complex Computational Biology Computer Models Computing Methodologies Coupling Daptomycin Data Development Drug Targeting Engineering Enzymes Escherichia coli Fatty Acids Fatty-acid synthase Future Goals Hybrids Immunosuppressive Agents In Vitro Knowledge Methodology Methods Microbe Modeling Modernization Modification Molecular Monitor Movement Multiple Partners Mutagenesis Natural Products Nature Organism Pathway interactions Peptide Biosynthesis Peptides Pharmaceutical Preparations Prevalence Prodigiosin Production Productivity Proteins Role Specificity Structure System Therapeutic Training Work X-Ray Crystallography antimicrobial clinically relevant combinatorial design genetic technology genome sequencing holo-(acyl-carrier-protein) synthase in vivo methicillin resistant Staphylococcus aureus microbial novel peptide synthase polyketide synthase practical application programs protein complex protein protein interaction rational design scaffold simulation structural biology success tool

项目摘要

Abstract: Natural products and derivatives/mimics of natural products make up the majority of modern therapeutic drugs due to their unique complex organic scaffolds that contribute to their wide range of bioactivities. These natural products are synthesized by the fatty acid synthase (FAS), the nonribosomal peptide synthetase (NRPS) or the polyketide synthase (PKS). This program studies the role of protein•protein interactions in the modular synthases responsible for the formation of clinically relevant fatty acids and nonribosomal peptides for the long-term goal of re-designing and completely controlling the biosynthetic assembly lines. An example of a natural product therapeutic in the clinic is the antimicrobial daptomycin, which is a lipopeptide synthesized from a hybrid fatty acid synthase (FAS) and nonribosomal peptide synthetase (NRPS) that is used to treat methicillin- resistant Staphylococcus aureus. Thus, the hybrid FAS/NRPS are valuable systems to study and control so we may diversify natural products with new or enhanced bioactivities. Over the last three decades, true control over the biosynthetic assembly lines has remained elusive; the lack of a fundamental understanding on how the mega- synthase’s protein•protein interactions govern natural product biosynthesis has hindered this promising advance. In order to control and develop a hybrid FAS/NRPS biosynthetic pathway, first we must understand the fundamentals that guides the related biosynthetic machinery. Both FASs and NRPSs are dependent on the carrier protein (CP); the CP shuttles the growing substrate between multiple partner proteins (PP) for functionalization and incorporation into the natural product. The modular nature of fatty acid and nonribosomal peptide biosynthesis is conserved among organisms, however, the mechanism of CP•PP recognition in each pathway is distinct. Thus, to re-design these biosynthetic assembly lines, this project focuses on studying the molecular details of the CP•PP interface. We aim to 1) Characterize NRPS CP•PP interactions via X-ray crystallography, 2) establish a computational methodology to design a hybrid NRPS/FAS interaction, and 3) explore the cross-pathway productivity of the hybrid NRPS/FAS interaction. The results from these studies will be integral to the future bioengineering of these modular synthases.

翻译后摘要：天然产物和天然产物的衍生物/模拟物构成了现代的大部分，由于其独特的复杂的有机支架，有助于其广泛的生物活性，治疗药物。这些天然产物是由脂肪酸合成酶（FAS），即非核糖体肽合成酶合成的（NRPS）或聚酮合酶（PKS）。该计划研究蛋白质·蛋白质相互作用在蛋白质中的作用。负责形成临床相关脂肪酸和非核糖体肽的模块化脂肪酶，重新设计和完全控制生物合成装配线的长期目标。的示例临床上的天然产物治疗剂是抗微生物达托霉素，其是由以下合成的脂肽：一种用于治疗甲氧西林的杂合脂肪酸合成酶（FAS）和非核糖体肽合成酶（NRPS），耐药金黄色葡萄球菌因此，混合FAS/NRPS是值得研究和控制的系统，可能使天然产品多样化，具有新的或增强的生物活性。在过去的三十年里，真正控制生物合成装配线仍然难以捉摸;缺乏对大型生物合成如何进行的基本理解，合成酶的蛋白质-蛋白质相互作用控制天然产物的生物合成，阻碍了这一有前途的进展。为了控制和开发杂交FAS/NRPS生物合成途径，首先我们必须了解指导相关生物合成机制的基本原理。FAS和NRPS都依赖于载体蛋白（CP）; CP在多个伴侣蛋白（PP）之间穿梭生长底物，功能化和掺入天然产物中。脂肪酸和非核糖体的模块性质肽的生物合成在生物体中是保守的，然而，CP·PP在每个生物体中的识别机制是不同的。路是不同的。因此，为了重新设计这些生物合成装配线，本项目重点研究了 CP·PP界面的分子细节。我们的目标是：1）通过X射线表征NRPS CP·PP相互作用晶体学，2）建立计算方法来设计杂化NRPS/FAS相互作用，以及3）探索杂合NRPS/FAS相互作用的跨途径生产力。这些研究的结果将成为这些模块化酶的未来生物工程的组成部分。