Directing Biosynthesis with Modular Architecture in Terpenoid Cyclases
发布时间 :2018-05-21  阅读次数 :5511

题  目:Directing Biosynthesis with Modular Architecture in Terpenoid Cyclases

报告人:David W. Christianson 教授  University of Pennsylvania

时  间:2018年5月23日,3:00 - 4:30 pm

地 点:徐汇校区哲生馆会议室



CV: Professor David Christianson received the AB, AM, and PhD from Harvard University before moving to the University of Pennsylvania, where he has been a member of the faculty for 28 years. His current research focuses on structural and function of metal-dependent arginases, deacetylases, and enzymes of terpenoid biosynthesis. At present, he had published series of papers in top professional journals such as Science, Nature, Nature Structural Biology, JACS, PNAS, Nature Communication.His accomplishments have been recognized by numerous awards, including the Pfizer Award in Enzyme Chemistry and the Repligen Award in Chemistry of Biological Processes from the American Chemical Society, and Fellowships from the John Simon Guggenheim Memorial Foundation, the Radcliffe Institute for Advanced Study at Harvard University, and the visiting Professor of Chemistry and Chemical Biology of Harvard University.Directing Biosynthesis with Modular Architecture in Terpenoid Cyclases David W. Christianson Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323


Abstract: Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that on average, two-thirds of the carbon atoms in an isoprenoid substrate undergo changes in bonding and/or hybridization during a multi-step cyclization cascade typically proceeding through multiple carbocation intermediates. Although the substrate pool for these enzymes is limited to only a handful of linear isoprenoids, more than 80,000 terpenoid natural products have been identified to date. This exquisite chemodiversity arises in part from the promiscuity of terpenoid biosynthesis, i.e., the ability of a cyclase to generate multiple products – sometimes utilizing different active sites that have evolved in different domains of a common protein fold. Crystal structures of terpenoid cyclases reveal modular architectures and catalytic strategies for carbocation generation, stabilization, and manipulation. Correlation of terpenoid cyclase structures and product arrays sets the foundation for understanding the biosynthetic code that directs the chemistry of carbon-carbon bond formation. As we decipher this code, we enable synthetic biology approaches for the large-scale generation of terpenoid natural products useful as pharmaceuticals, fragrances, flavorings, and fuels.

Crystal structures of taxadiene synthase and ent-copalyl diphosphate synthase reveal identical protein folds. However, the active site of taxadiene synthase is in the a domain (blue), where it catalyzes the metal-dependent ionization and cyclization of geranylgeranyl diphosphate; the active site of ent-copalyl diphosphate synthase is at the interface of the b and g domains (green and yellow, respectively), where it catalyzes the protonation-dependent cyclization of geranylgeranyl diphosphate.