CRYSTAL STRUCTURES OF POLYKETIDE SYNTHASE FOR COMBINATORIAL BIOSYNTHESIS OF ANTI

用于抗组合生物合成的聚酮合成酶的晶体结构

• 批准号: 8169927
• 负责人: Shiou-Chuan Tsai
• 金额: $ 0.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169927
• 关键词: Anabolism; Antibiotics; Aromatase; Biological Factors; Computer Retrieval of Information on Scientific Projects Database; Daunorubicin; Funding; Grant; Institution; Length; Malignant Neoplasms; Methods; Multienzyme Complexes; Mutation; Research; Research Personnel; Resources; Selenomethionine; Source; Structure; Tetracyclines; United States National Institutes of Health; Variant; antineoplastic antibiotics; combinatorial; griseusin; novel; polyketide synthase

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polyketide synthase, a multi-domain enzyme complex, makes many anticancer and antibiotic natural products in a combinatorial fashion by domain shuffling. Polyketide synthase is capable of generating huge variety of ?unnatural? natural products via a controlled variation of chain length and regio-specific formation of rings. Crystal structures of the polyketide synthase components are crucial for such maneuver. Aromatase (ARO) is the key component that controls the formation of aromatic ring of many anti-cancer and antibiotic polyketides, such as daunorubicin, griseusin and tetracycline in a highly specific manner (C7-C12 or C9-C14), however no crystal structure is available for ARO. ARO structure will enable mutations to alter the regiospecificity of ring formation (e.g. C11-C16). Native ARO crystals diffracted to 2.0 ¿. KBr, NaI and selenomethionine-derivatized ARO crystals were also grown. In addition, we obtained crystals of the chain elongation domain (ZhuH) and extender unit domain (FkbI and FkbG). Beamtime at SSRL will be vital for us to solve the crystal structure ARO, ZhuH, FkbI and FkbG using MR, MAD or MIR methods. These polyketide synthase domain structures will be utilized in a combinatorial fashion to generate novel anticancer and antibiotic drug leads.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 聚酮合酶是一种多结构域酶复合物，通过结构域改组以组合方式产生许多抗癌和抗生素天然产物，聚酮合酶能够通过链长度和区域特异性的受控变化产生多种“非天然”产物。聚酮合酶成分的晶体结构对于这种操作至关重要，它是控制许多抗癌和抗生素芳香环形成的关键成分。聚酮化合物，例如柔红霉素、灰红霉素和四环素，以高度特异性的方式（C7-C12 或 C9-C14），但是 ARO 没有可用的晶体结构，ARO 结构将使突变能够改变环形成的区域特异性（例如 C11-C16）。 ). 原生 ARO 晶体衍射至 2.0 ¿此外，我们还生长了 KBr、NaI 和硒代蛋氨酸衍生的 ARO 晶体。此外，我们在 SSRL 获得了链延伸结构域 (ZhuH) 和延伸单元结构域 (FkbI 和 FkbG) 的晶体，这对于我们解决晶体结构至关重要。使用 MR、MAD 或 MIR 方法将获得 ARO、ZhuH、FkbI 和 FkbG 这些聚酮化合物合酶结构域。以组合方式用于产生新型抗癌和抗生素先导药物。