Exploring Post-Type II PKS Frame Modifications

探索 Post-Type II PKS 框架修改

• 批准号: 9110311
• 负责人: Jurgen T Rohr
• 金额: $ 27.67万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110311
• 关键词: Address; Anabolism; Anthracyclines; Antibiotics; Antineoplastic Agents; Biochemical; Biological; Catalysis; Characteristics; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Collaborations; Communicable Diseases; Complex; Development; Drug Interactions; Effectiveness; Engineering; Enzyme Interaction; Enzymes; Epirubicin; Event; Evolution; Future; Generations; Goals; Health; In Vitro; Investigation; Kentucky; Laboratories; Lead; Malignant Neoplasms; Methods; Methylation; Michigan; Modeling; Modification; Molecular; Multienzyme Complexes; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Product Drug; Natural Products; Nature; Oxidoreductase; Oxygenases; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Pharmacy facility; Plicamycin; Proteins; Reaction; Recombinant Proteins; Regimen; Resistance; Side; Skeleton; System; Tetracyclines; United States National Institutes of Health; Universities; Vertebral column; Work; analog; antineoplastic antibiotics; base; cancer therapy; catalyst; chemotherapy; college; combinatorial; cost; drug discovery; drug synthesis; expectation; glycosylation; glycosyltransferase; improved; interest; member; novel; novel therapeutics; overexpression; polyketide synthase; protein structure; receptor; resistance mechanism; scaffold; screening; tigecycline; tool; transamination

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.

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，具有选择性匹配生物受体的潜力。天然产物对癌症和传染病的治疗特别有用，但迫切需要新的药物，因为目前的药物治疗方案不可避免地由于耐药机制而失去效力。许多重要的天然产物药物是由聚酮合成酶（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。II型pks将多环芳香族中间体与相应的剪裁酶组装在一起，负责重要药物的生成，如临床上使用的四环素类抗生素，或蒽环类和金果酸类抗癌药物。虽然II型pks研究得很好，但pks后的步骤知之甚少，尽管框架修饰酶通常将惰性支架转化为生物活性药物。本提案的主要目标是在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，这些酶参与抗癌多酮类药物的生物合成，包括氨环素和金酚酸基团。我们希望揭示催化的分子细节