Development of novel halogenase enzymes for biopharmaceutical applications

鉴定新的卤化合成、天然和非天然化合物；进一步开发和合成这些化合物在当今时代具有极其重要的意义。这是由于有机卤化物在各种有机反应中作为药物、农用化学品和有价值的合成物发挥着深远的作用。卤化分子作为有机合成中间体，在许多金属催化的交叉偶联反应中起着特别重要的作用。自然界已经进化出许多生物催化剂，以区域选择性地卤化各种生物合成前体和次生代谢物，这种未开发的功能正在不断增长。生物合成卤化可以发生在天然化合物的简单到极其复杂的环结构上，在某些情况下，它引发了复杂结构和支架的形成。这些反应通常从简单的芳香取代到复杂的立体选择性碳氢官能化和远端碳中心的活化。这些可靠、简便、清洁的生物合成途径与传统的需要有害试剂和缺乏区域控制的非酶卤化化学相比，具有潜在的实用性和更大的需求。在过去的几年里，我们已经通过基因组挖掘在天然产物途径中确定了一些重要的药物卤化酶系统。在这个项目中，我们计划探索它们的酶结构，底物范围以及它们在有机合成中的潜在应用。最终目标是将这些酶纳入合成和生物合成途径，并纳入生物技术和制药应用的各种天然产物途径。

Identification of new halogenated synthetic, natural and non-natural compounds; and further exploitation and synthesis of these compounds are of extreme importance in this modern era. This is due to the profound role of organohalides as pharmaceuticals, agrochemicals and valuable synthons in various organic reactions. As organic synthetic intermediates, halogenated molecules are of particular importance in many metal-catalysed cross-coupling reactions. Nature has evolved a number of biocatalysts to regioselectively halogenate a diverse range of biosynthetic precursors and secondary metabolites, and this unexplored repertoire is ever growing. Biosynthetic halogenation can occur over simple to extremely complex ring structures of natural compounds and in some cases, it initiates the formation of complex structures and scaffolds. These reactions often range from simple aromatic substitutions to complex stereoselective C-H functionalization and activation of remote carbon centres. These reliable, facile and cleaner biosynthetic routes have potential utility and greater demand over traditional nonenzymatic halogenation chemistry that requires deleterious reagents and lacks regio-control. In the past few years we have identified a number of pharmaceutically important halogenase systems by genome mining in natural product pathways. In this project, we are planning to explore their enzyme structure, substrate scope along with their potential applications in organic synthesis. The ultimate aim is to incorporate these enzymes in to synthetic and biosynthetic pathways and into various natural product pathways for biotechnological and pharmaceutical applications.