Elucidating and Engineering Legonmycin Biosynthesis: a framework for heterobicyclic biotransformation

我们目前用于治疗癌症、细菌感染、免疫紊乱和病毒感染的许多药物要么是天然产物，要么是从天然产物中提取的。因此，天然产物仍然是开发新药和诊断分子先导化合物的主要来源。然而，天然产物在结构和组成方面往往是复杂的，这使得合成化学家很难获得它们并因此进一步发展。相比之下，细菌可以拥有有机化学家梦寐以求的复杂化学物质的惊人库存。在制造新分子的过程中，一个关键的挑战往往是确定合理的新支架或基序（也称为化学多样性），这是药物发现的核心。我们将研究两种细菌酶，它们具有在温和的反应条件下将线性肽转化为杂双环分子的能力。这些杂双环系统是生物学上重要的化合物中常见的基序，但目前还没有很好的合成化学方法。利用细菌酶来完成化学任务在食品工业中已经很好地建立了，并且在可持续生产方面的好处也得到了很好的证明。然而，酶法/工业生物技术在精细化工、制药和农业等行业的应用仍未得到充分发展。通过研究这两种酶的催化能力，我们将获得开发其工业生物技术潜力的能力。通过这样做，我们将能够制造新的构建块（也称为支架），并获得新的生物活性化合物。

Many currently used drugs that we rely on for the treatment of cancer, bacterial infection, immune disorders and viral infections are either natural products or are derived from natural products. As such natural products still remain the major source of lead compounds for the development of new drugs and diagnostic molecules. However, natural products are often complex in terms of structure and composition making them difficult for synthetic chemists to access and thus develop further. In contrast bacteria can possess an amazing inventory of complex chemistry that organic chemists only dream of. In making new molecules, a key challenge is often to identify plausible new scaffolds or motifs (also known as chemical diversity) which is at the heart of drug discovery. We are going to study two bacterial enzymes that have the capability to convert linear peptide into heterobicyclic molecules under mild reactive conditions. These heterobicyclic ring systems are a common motif in biologically important compounds but there does not have any good way of making them by synthetic chemistry. The use of the bacterial enzymes to accomplish chemical tasks is well established in food industry and the benefits in terms of sustainable manufacturing are well document. However, the application of enzymatic process/ industrial biotechnology processes are still under developed the fine chemical, pharmaceutical and agricultural industries. By working out the catalytic capabilities of the two enzymes we will gain the ability to develop their industrial biotechnological potential. In doing this, we will be able to make novel building blocks (also known as scaffolds) and, access new biologically active compounds.