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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 聚酮化合物合酶是一种多域酶复合物，以结构域进行的组合方式以组合方式制作了许多抗生素和抗生素天然产物。 Polyketide合酶能够产生多种不自然的？天然产物通过链长的控制变化和环的区域特异性形成。聚酮化合酶成分的晶体结构对于这种操作至关重要。芳香酶（ARO）是控制许多抗癌和抗生素聚酮化合物的芳族环的关键成分，例如Daunorubicin，Griseusin和Tetracycline以高度特异性的方式（C7-C12或C9-C14），但是ARO无需使用晶体。 ARO结构将使突变能够改变环形成的调节特异性（例如C11-C16）。天然ARO晶体衍射为2.0。还种植了KBR，NAI和硒甲米汀的ARO晶体。此外，我们获得了链伸长域（Zhuh）和扩展单位域（FKBI和FKBG）的晶体。 SSRL的Beamtime对于我们使用MR，MAD或MIR方法解决晶体结构ARO，Zhuh，FKBI和FKBG至关重要。这些聚酮化合物合酶结构结构将以组合方式用于产生新型的抗癌和抗生素药物铅。