Lipoxygenases and Diversity in Oxylipin Biosynthesis

智力优势：氧脂素是一种信号化合物，在动物、植物、真菌和蓝藻中介导一系列防御机制。它们来源于多不饱和脂肪酸，它们的合成是由称为脂氧合酶的酶的作用引发的。脂氧合酶催化反应的产物通过另外的酶的作用进一步转化为活性信号分子。由脂氧合酶催化的反应非常精确：在非酶促反应中，该酶只能产生多种产物中的一种。该研究旨在提供不同的脂氧合酶如何从相同的起始化合物产生不同产物的三维理解。此外，脂氧合酶通常表达为双功能蛋白质，即酶与第二催化结构域融合，其进一步转化脂氧合酶产物。因此，氧化脂质在自然界中的化学多样性进一步扩大。这项研究将揭示催化机制，产生显着多样性的化合物产生的双功能脂氧合酶。知识的结构基础的高度新颖的化学进行这类独特的酶将提供手段，利用单和双功能脂氧合酶的天然产物的合成，或其衍生物，生产杀虫剂和抗真菌剂。更广泛的影响：研究形成一个长期的承诺，研究和教育的整合的重要组成部分。虽然研究生将主要负责研究的执行，本科生将继续为进步做出重要贡献，各级学生将广泛接触最先进的技术和在分子水平上理解生物过程的综合方法。在一定水平上理解分子机制，使人们能够利用自然的工具来改善生活在其中的世界，需要结合不同的方法。虽然这种跨学科努力的需求推动了所谓的“团队”科学，但这样的培训环境并不一定适合年轻的研究人员，因为如果他们在子学科之间的移动被认为不符合成本效益，那么它可以很容易地促进高度专业化的培训。在研究中，PI和学生并肩工作，联合收割机结合结构生物学，生物化学和分子生物学的方法，以解决在氧脂素生物合成的关键酶的结构/功能关系方面。

Intellectual Merit: Oxylipins are signaling compounds that mediate an array of defense mechanisms in animals, plants, fungi and cyanobacteria. They are derived from polyunsaturated fatty acids and their synthesis is initiated by the action of enzymes known as lipoxygenases. The product of the lipoxygenase catalyzed reaction is further transformed to the active signaling molecule by the action of additional enzymes. The reaction catalyzed by lipoxygenase is remarkably precise: the enzyme is able to generate only one of a number of products possible in a non-enzymatic reaction. The research is aimed at providing a three-dimensional understanding of how different lipoxygenases can generate a distinct product from the same starting compound. In addition, lipoxygenases are often expressed as bi-functional proteins, i.e. the enzyme is fused to a second catalytic domain which further transforms the lipoxygenase product. Thus the chemical diversity of oxylipins in nature is further expanded. This research will reveal the catalytic machinery that produces the remarkable diversity of compounds produced by bi-functional lipoxygenases. Knowledge of the structural basis of the highly novel chemistries performed by this unique class of enzymes will provide the means to exploit mono and bi-functional lipoxygenases for the synthesis of natural products, or derivatives thereof, to produce pesticides and anti-fungals.Broader Impacts: The studies form an essential part of a long term commitment to the integration of research and education. While graduate students will primarily be responsible for execution of the research, undergraduates will continue to make important contributions to progress and students at all levels will gain broad exposure to both state-of-the-art techniques and an integrative approach to understanding biological processes at the molecular level. Understanding molecular mechanisms at a level that allows one to exploit the tools of nature to improve the world in which lives requires combining diverse approaches. While this need for an interdisciplinary effort has fueled what may be termed "team" science, such a training environment is not necessarily hospitable for young investigators as it can easily foster highly specialized training if their movement between sub-disciplines is not deemed cost effective. In the studies the PI and students work side by side to combine methods in structural biology, biochemistry and molecular biology to address aspects of structure/function relationships in key enzymes in oxylipin biosynthesis.