Structure and Function of Animal Polyketide Synthases: Bridging Lipid and Polyketide Biology

动物聚酮化合物合成酶的结构和功能：桥接脂质和聚酮化合物生物学

• 批准号: 2203613
• 负责人: Eric Schmidt
• 金额: $ 72.3万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2203613&HistoricalAwards=false
• 关键词: Structure; Function; Animal; Polyketide; Synthases

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Dr. Eric Schmidt and collaborator Dr. Chris Hill from the University of Utah investigate molecular principles of how lipids are biosynthesized in animals and in humans. While the biochemical basis of fatty acid biosynthesis has long been studied, recently, new families of enzymes that create chemically diverse lipids have been uncovered in mammalian genomes. These enzymes address a biosynthetic challenge that bridges the gap between polyketides, structurally elaborate compounds that are used as pharmaceuticals, and the structurally simpler major fats found in humans and animals. The proposed experiments represent a new direction synthetic biology and are expected to provide a molecular-level understanding these interesting mammalian polyketide synthase and provide new tools for lipid and polyketide engineering and discovery. These studies will contribute to high level postdoctoral fellow training at the interface of chemistry and biology, with specialized training in the science of cryo-electron microscopy and advanced structural techniques. A summer training program will introduce high school students to structural biology.This research project seeks to understand the structure and function of novel polyketide synthases found in mammalian biology, including human biology. The enzymes will be characterized in vitro using biochemical methods, such as kinetic analysis with different substrates and cofactors and determination of the structures of the novel products of these enzymes. Cryo-electron microscopy studies will be applied to determine the enzyme structures, which will be followed up by hypothesis-guided mutational analyses. Taken together, these studies will determine the structural principles underlying mammalian polyketide synthase substrate and product selectivity. Further, the Schmidt and Hill team will compare the results obtained in the study of mammalian systems with those from human fatty acid synthase, using the results to build new lipid derivatives by designed engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系生命过程化学（CLP）项目的支持下，来自犹他州大学的Eric施密特博士和合作者Chris Hill博士研究了脂质在动物和人类中生物合成的分子原理。虽然脂肪酸生物合成的生物化学基础已经研究了很久，但最近在哺乳动物基因组中发现了产生化学多样性脂质的新酶家族。这些酶解决了生物合成的挑战，弥合了聚酮化合物（用作药物的结构复杂的化合物）与人类和动物中结构简单的主要脂肪之间的差距。这些实验代表了合成生物学的一个新方向，有望从分子水平上了解这些有趣的哺乳动物聚酮合酶， 为脂质和聚酮化合物的工程和发现提供了新的工具。这些研究将有助于在化学和生物学的接口高水平的博士后研究员培训，在冷冻电子显微镜和先进的结构技术的科学专门培训。本研究课题旨在通过暑期实习向高中生介绍结构生物学。本研究课题旨在了解哺乳动物生物学（包括人类生物学）中发现的新型聚酮酶的结构和功能。将使用生物化学方法在体外对酶进行表征，例如使用不同底物和辅因子的动力学分析以及确定这些酶的新产物的结构。冷冻电子显微镜研究将用于确定酶的结构，随后将进行假设指导的突变分析。总之，这些研究将确定哺乳动物聚酮合酶底物和产物选择性的结构原则。此外，施密特和希尔团队还将对哺乳动物系统的研究结果与人类脂肪酸合成酶的研究结果进行比较，利用这些结果通过设计工程构建新的脂质衍生物。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。