CRYSTAL STRUCTURES OF POLYKETIDE SYNTHASE FOR COMBINATORIAL BIOSYNTHESIS OF ANTI

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 聚酮合成酶是一种多结构域的酶复合体，通过结构域改组使多种抗癌和抗菌天然产物结合在一起。聚酮合成酶能够产生大量的非自然的？通过可控的链长变化和特定区域的环形成的天然产物。聚酮合成酶成分的晶体结构对这种操作至关重要。芳香化酶(Aromatase，ARO)是控制柔红霉素、灰霉素和四环素等多种抗癌和抗生素多酮类化合物芳香环形成的关键组分，具有很高的特异性(C7-C12或C9-C14)，但其晶体结构尚未确定。Aro结构将使突变能够改变环形成的区域特异性(例如C11-C16)。天然的ArO晶体衍射率为2.0°。还生长了KBr、NaI和硒蛋氨酸衍生的ARO晶体。此外，我们还得到了链延长结构域(ZHH)和扩展单元结构域(FkbI和FkbG)的晶体。SSRL的束流时间对于我们用MR、MAD或MIR方法求解晶体结构ARO、ZHH、FkbI和FkbG将是至关重要的。这些聚酮合成酶结构域结构将以组合的方式被用来产生新的抗癌和抗菌药物先导。

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.