Using the Marine Natural Product Psymberin as a Discovery Template for Biosynthetic Engineering and Biosynthetic Product Investigation

本申请的目标是启动美国和德国学术科学家之间的生物有机化学合作研究计划。由Phil Crews教授领导的美国加州大学圣克鲁斯分校化学与生物化学系海洋天然产物小组将与由Joern Piel副教授领导的德国波恩大学Kekule有机化学与生物化学研究所海洋生物合成工程小组并肩工作。2004年，克鲁斯实验室报道了从巴布亚新几内亚收集的沙门菌海绵中分离出的灵麻素的结构。海洋天然产物石芹素似乎是不规律地产生的，并与陆地衍生的pederin家族化合物有关。2005年，Piel小组构建了fuscipes Paederus甲虫和海绵Theonella swinhoei的宏基因组文库，并分离出了pederin及其相关类胺生物合成所需的基因。这项研究的目的是将这项技术扩展到药理学上非常有前途的海洋系统。包括可能的微生物共生体在内的产麻黄素海绵将成为六个项目目标的基础：(1)通过探索沙尘菌的化学型和形态型，全面确定PKS-NRPS产品麻黄素类的结构多样性；(2)将海绵中灵麻素的出现与其微生物种群联系起来；（三）从事灵麻素基因的分离、测序和表达；(4)利用目标#2和#3的结果寻找产生灵麻素的微生物菌株；(5)让美国和德国学生了解合作研究的优势和过程；(6)为美国和德国学生提供关于科学伦理的观点。通过这一奖项，有机和大分子化学项目和国际科学与工程办公室支持加州大学圣克鲁斯分校化学与生物化学系的菲利普O.克鲁斯教授的工作。克鲁斯教授和他的合作者，波恩大学凯库勒有机化学和生物化学研究所的约翰·皮尔，正在探索海洋海绵合成一组不同寻常的分子的方法，这些分子在结构上与陆地生物产生的一类分子有趣地相关。这项研究将解决海洋生物有机化学中尚未解决的问题，从而了解海洋生物如何产生如此复杂的分子，这通常会导致新药物制剂的发现。需要广泛的技能集，这只能通过协作方法来完成。该项目的成功将成为国际学术合作研究的典范，并将证明海洋化学生物学的多国合作可以取得成功。

The goal of this application is to launch a cooperative research program in bioorganic chemistry between U.S. and German academic scientists. The Marine Natural Products group at the University of California Santa Cruz, Department of Chemistry and Biochemistry, in the USA led by Professor Phil Crews will work side-by-side with the Marine Biosynthetic Engineering group at the Kekule Institute of Organic Chemistry and Biochemistry, University of Bonn, in Germany led by Associate Professor Joern Piel. In 2004, the Crews lab reported the structure of psymberin isolated from Psammocinia sp. sponges collected in Papua New Guinea. The marine natural product psymberin appears to be erratically produced and is related to the terrestrial-derived pederin family of compounds. In 2005, the Piel group constructed metagenomic libraries of Paederus fuscipes beetles and the sponge Theonella swinhoei and was able to isolate the genes required for the biosynthesis of pederin and the related onnamides. The intent of this proposed research is to extend this technology to a pharmacologically highly promising marine system. The psymberin-producing sponge including possible microbial symbionts will be the basis for the six program goals that are: (1) to fully define the structural diversity of the psymberin class of PKS-NRPS products by exploring chemotypes and morphotypes of Psammocinia sp.; (2) to correlate the appearance of psymberin in sponges with its microbial populations; (3) to engage in the isolation, sequencing, and expression of psymberin genes; (4) to use the results of aims #2 and #3 to search for psymberin producing microbial strains; (5) to expose USA and German students to the advantages and process of collaborative research; and (6) to provide USA and German students perspectives on ethics in science.With this award, the Organic and Macromolecular Chemistry Program and the Office of International Science and Engineering are supporting the work of Professor Phillip O. Crews, of the Department of Chemistry and Biochemistry at the University of California at Santa Cruz. Professor Crews and his collaborator, Joern Piel, of the Kekule Institute of Organic Chemistry and Biochemistry at the University of Bonn, are exploring the means by which marine sponges synthesize an unusual group of molecules intriguingly related structurally to a class of molecules produced by terrestrial organisms. This study will address unanswered questions of marine bioorganic chemistry, leading to an understanding of how marine organisms produce such complex molecules, which not infrequently lead the way to the discovery of new pharmaceutical agents. A broad skill set is required and this can only be done through a collaborative approach. The success of this program will serve as a model for international scholarly collaborative research and will demonstrate that a multinational collaboration in marine chemical biology can be successful.