Exploring Post-Type II PKS Frame Modifications

描述（由申请人提供）：天然产物对药物发现有重大影响。在1940年至2006年期间，它们贡献了大约50%的新化学实体，因为它们提供了独特的丰富的结构骨架，结合了高度的手性，具有选择性匹配生物受体的潜力。天然产物对于治疗癌症和传染病特别有用，然而迫切需要新的药物，因为目前的药物方案由于耐药性机制而不可避免地失去其有效性。许多重要的天然产物药物是通过聚酮酶（PKS，多酶复合物）和各种框架修饰反应（称为PKS后剪裁步骤）产生的。组装多环芳香族中间体的II型PKS与相应的剪裁酶一起负责重要药物的产生，例如临床上使用的四环素抗生素或蒽环类和金酸抗癌药物。虽然II型PKS已被充分研究，但PKS后步骤的理解要少得多，尽管框架修饰酶通常将惰性支架转化为生物活性药物。该提案的主要目标是功能和机制上表征独特的反应和有组织的框架修饰后PKS酶参与的angucycline和aureolic acid基团的抗癌聚酮药物的生物合成。我们期望揭开催化作用的分子细节， 有助于进化这些关键酶，以便它们可以用于修饰II型PKS支架。这可以通过组合生物合成、突变合成或化学-酶促合成策略产生新的第二代“非天然”天然产物和/或天然产物的衍生物。这些研究还将有助于产生新的光辉霉素和gilvocarcin类似物，这将有助于进一步研究和指导这些药物与其最近发现的特定靶点的相互作用。

DESCRIPTION (provided by applicant): Natural products have a major impact on drug discovery. They have contributed to approximately 50% of new chemical entities between 1940 and 2006, because they offer a unique richness in structural skeletons combined with a high degree of chirality that has the potential to selectively match bio-receptors. Natural products have been particularly useful for the treatment of cancer and infectious diseases, nonetheless new drugs are urgently needed because current drug regimens inevitably lose their effectiveness due to resistance mechanisms. Many important natural product drugs are generated by polyketide synthases (PKS, multiple enzyme complexes), and various frame-modifying reactions, called post-PKS tailoring steps. Type II PKSs assembling multicyclic aromatic intermediates together with the respective tailoring enzymes are responsible for the generation of important drugs, such as the clinically used tetracycline antibiotics, or anthracycline and aureolic acid anticancer drugs. While type II PKSs are well studied, the post-PKS steps are much less understood, although the frame modifying enzymes typically render an inert scaffold into a bioactive drug. The primary goal of this proposal is to functionally and mechanistically characterize uniquely reacting and organized frame modifying post-PKS enzymes involved in the biosynthesis of anticancer polyketide drugs of the angucycline and aureolic acid groups. It is our expectation that uncovering the molecular details of catalysis will help to evolve these critical enzymes, so that they can be exploited to modify type II PKS scaffolds. This could lead to novel, second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis, mutasynthesis, or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.