Elucidating and Engineering Legonmycin Biosynthesis

我们治疗癌症和感染所依赖的许多药物要么是天然产品，要么来自天然产品。因此，天然产品仍然是开发新药的主要先导化合物来源。然而，天然产物的结构往往很复杂，使得合成化学家很难接触到它们。相比之下，细菌拥有令人惊叹的复杂化学清单，这是有机化学家只能梦想的。我们将研究两种细菌酶，它们能够在温和的反应条件下将线性多肽转化为杂双环分子。这些杂双环是许多生物上重要和工业上相关的分子的关键成分。我们将通过使用具有不同立体产生中心的底物和通过活性部位的现场直接突变来推进我们最初的机械工作。底物耐受性是工业生物催化剂成功的关键特征，我们将合成配备不同化学手柄的多肽硫酯，并探索目标酶的底物灵活性。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，并能够获得新的生物活性支架。

Many drugs that we rely on for the treatment of cancer, and infections are either natural products or are derived from natural products. As such natural products remain a major source of lead compounds for the development of new drugs. However, natural products are often complex in terms of their structure making it difficult for synthetic chemists to access them. In contrast bacteria possess an amazing inventory of complex chemistry that organic chemists can only dream of. We will study two bacterial enzymes that have the capability to convert linear peptides into heterobicyclic molecules under mild reactive conditions. These heterobicyclic rings are critical components of many biologically important and industrially relevant molecules. We will advance our initial mechanistic work by using substrates with different stereogenic centres and through site direct mutagenesis of the active site. Substrate tolerance is a key feature for a successful industrial biocatalyst and we will synthesize peptide thioesters equipped with different chemical handles and probe the substrate flexibility of the target enzymes. By working out the catalytic capabilities of the two enzymes we will gain the ability to develop their industrial biotechnological potential and be able to access new biologically active scaffolds.