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: 7954187
• 负责人: Shiou-Chuan Tsai
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954187
• 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; structural biology; synchrotron radiation

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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合成多种抗癌和抗生素天然产物。聚酮合酶能够产生大量的？不自然？通过控制链长的变化和环的区域特异性形成来合成天然产物。聚酮合酶组分的晶体结构对于这种操作是至关重要的。芳香化酶（Aromatase，ARO）是许多抗癌和抗生素聚酮化合物（如柔红霉素、灰霉素和四环素）芳香环形成的关键组分，具有高度特异性（C7-C12或C9-C14），但目前还没有其晶体结构。ARO结构将使突变能够改变环形成的区域特异性（例如C11-C16）。天然ARO晶体衍射至2.0 º。还生长了KBr、NaI和硒代甲硫氨酸衍生的ARO晶体。此外，我们获得了链延伸结构域（ZhuH）和扩展单元结构域（FkbI和FkbG）的晶体。SSRL的束流时间对于我们使用MR、MAD或MIR方法求解ARO、ZhuH、FkbI和FkbG的晶体结构至关重要。这些聚酮合酶结构域结构将以组合方式用于产生新的抗癌和抗生素药物先导物。