Development of novel halogenase enzymes for biopharmaceutical applications

鉴定新的卤代合成、天然和非天然化合物，以及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作为药物、农用化学品和有价值的合成子在各种有机反应中的深刻作用。作为有机合成中间体，卤代分子在许多金属催化的交叉偶联反应中具有特别重要的作用。自然界已经进化出许多生物催化剂来区域选择性地卤化一系列不同的生物合成前体和次生代谢物，并且这一未被探索的曲目还在不断增长。生物合成卤代反应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，它会引发复杂结构和支架的形成。这些反应的范围通常从简单的芳香取代到复杂的立体选择性C-H官能化和远程碳中心的活化。与传统的非酶卤化反应相比，这些可靠、简便、清洁的生物合成路线具有潜在的用途和更大的需求，因为传统的非酶卤化反应需要有害的试剂，而且缺乏区域控制。在过去的几年里，我们通过在天然产物途径中进行基因组挖掘，鉴定了一些具有重要药用价值的卤代酶系统。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结合到合成和生物合成途径以及各种用于生物技术和制药应用的天然产品途径中。

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.