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

在化学系生命过程化学(CLP)项目的支持下，犹他大学的Eric Schmidt博士和他的合作者Chris Hill博士研究了动物和人类体内脂质生物合成的分子原理。虽然脂肪酸生物合成的生化基础已经被研究很久了，但最近，在哺乳动物基因组中发现了新的酶家族，它们可以产生化学上不同的脂类。这些酶解决了生物合成的挑战，弥合了多酮和人类和动物中发现的结构更简单的主要脂肪之间的差距。多酮是一种结构复杂的化合物，可用作药物。这些实验代表了合成生物学的一个新方向，有望从分子水平上理解这些有趣的哺乳动物聚酮合成酶，并为脂类和聚酮的工程和发现提供新的工具。这些研究将有助于化学和生物学交界处的高水平博士后研究员培训，并提供冷冻电子显微镜科学和先进结构技术方面的专门培训。暑期培训计划将向高中生介绍结构生物学。这项研究项目旨在了解在哺乳动物生物学，包括人类生物学中发现的新型聚酮合成酶的结构和功能。这些酶将在体外使用生化方法进行表征，例如不同底物和辅因子的动力学分析以及这些酶的新产物的结构测定。低温电子显微镜研究将用于确定酶的结构，随后将进行假说导向的突变分析。综上所述，这些研究将确定哺乳动物聚酮合成酶底物和产物选择性的结构原理。此外，Schmidt和Hill团队将比较在哺乳动物系统研究中获得的结果与从人类脂肪酸合成酶中获得的结果，利用这些结果通过设计的工程来构建新的脂肪衍生物。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.