Exploring Post-Type II PKS Frame Modifications

描述(申请人提供)：天然产品对药物发现有重要影响。在1940至2006年间，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，并结合了高度的手性，有可能选择性地匹配生物受体。天然产品对癌症和传染病的治疗特别有用，然而，由于目前的药物方案不可避免地由于耐药机制而失去效力，因此迫切需要新的药物。许多重要的天然产物药物是由聚酮合成酶(PKS，多酶复合体)和各种框架修饰反应产生的，称为PKS后剪裁步骤。第二类PKS将多环芳香族中间体与相应的剪裁酶组装在一起，负责产生重要的药物，如临床上使用的四环素类抗生素，或蒽环类和金酸类抗癌药物。虽然II型PKS研究得很好，但PKS后的步骤却鲜为人知，尽管框架修饰酶通常会将惰性支架转化为生物活性药物。这项建议的主要目的是从功能和机械上表征参与抗癌聚酮类药物生物合成的独特反应和有组织的骨架修饰后PKS酶。我们期望，揭示催化的分子细节将会 帮助进化这些关键的酶，以便它们可以被利用来修饰II型PKS支架。这可能导致通过组合生物合成、突变合成或化学-酶合成策略产生新颖的第二代“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米特拉霉素和吉尔沃卡星类似物，这些类似物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.