Nature2014-06-27 1:14 PM

模块化聚酮合酶的结构2 Structural rearrangements of a polyketide synthase module during its catalytic cycle

论文摘要 

聚酮合酶(PKSs)是生成聚酮(一大类次级代谢产物——换句话说就是天然产物)的多域酶复合物。来自Georgios Skiniotis及同事的两篇论文用低温电子显微镜来研究“委内瑞拉链霉菌”的苦霉素生物合成中所涉及的一个完好无损的全长度多酶PKS模块在不同功能状态下的结构。这些结构显示,酮基合酶、酰基转移酶、酮还原酶和酰基载体蛋白(ACP)域在催化周期中相互作用。在每一种状态,ACP 处于不同位置,来促进中间体向下一个催化步骤和下一个模块转移。

Abstract 

The polyketide synthase (PKS) mega-enzyme assembly line uses a modular architecture to synthesize diverse and bioactive natural products that often constitute the core structures or complete chemical entities for many clinically approved therapeutic agents. The architecture of a full-length PKS module from the pikromycin pathway of Streptomyces venezuelae creates a reaction chamber for the intramodule acyl carrier protein (ACP) domain that carries building blocks and intermediates between acyltransferase, ketosynthase and ketoreductase active sites (see accompanying paper). Here we determine electron cryo-microscopy structures of a full-length pikromycin PKS module in three key biochemical states of its catalytic cycle. Each biochemical state was confirmed by bottom-up liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry. The ACP domain is differentially and precisely positioned after polyketide chain substrate loading on the active site of the ketosynthase, after extension to the β-keto intermediate, and after β-hydroxy product generation. The structures reveal the ACP dynamics for sequential interactions with catalytic domains within the reaction chamber, and for transferring the elongated and processed polyketide substrate to the next module in the PKS pathway. During the enzymatic cycle the ketoreductase domain undergoes dramatic conformational rearrangements that enable optimal positioning for reductive processing of the ACP-bound polyketide chain elongation intermediate. These findings have crucial implications for the design of functional PKS modules, and for the engineering of pathways to generate pharmacologically relevant molecules.

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

Nature

Nature Magazine

0 Following 27 Fans 0 Projects 626 Articles

SIMILAR ARTICLES

Meristems encompass stem/progenitor cells that sustain postembryonic growth of all plant organs. How meristems are activated and sustained by nutrient

Read More

Transcription of ribosomal RNA by RNA polymerase (Pol) I initiates ribosome biogenesis and regulates eukaryotic cell growth. The crystal structure of P

Read More

Abstract The effect of anthropogenic aerosols on cloud droplet concentrations and radiative properties is the source of one of the largest uncertainti

Read More

Abstract Ecological and societal disruptions by modern climate change are critically determined by the time frame over which climates shift beyond his

Read More

Abstract Evidence from Greenland ice cores shows that year-to-year temperature variability was probably higher in some past cold periods, but there is

Read More

Abstract The land and ocean act as a sink for fossil-fuel emissions, thereby slowing the rise of atmospheric carbon dioxide concentrations1. Although t

Read More

论文摘要 人们已经非常清楚生物多样性对初级生产力等生态系统功能有一个积极影响,但它对植物凋落物的多样性和分解植物凋落物的生物的多样性的影响却不是很清楚。Stephan H?ttenschwiler及同事对从亚北极到热带、包括水生生态系统和陆地生态系统在内的五个地点所进行的并行操纵实验中的凋落物多样性进

Read More

论文摘要 FANTOM5 (即“哺乳动物基因组-5的功能注解”) 是一个大型国际合作项目的第5大阶段,其目标是分析定义每个人类细胞类型的转录调控网络。本期Nature上的两篇Articles论文发表了该项目的一些最新结果。第一篇论文利用FANTOM5项目组的组织和原代细胞样本来定义整个人体中活性的、在

Read More

论文摘要 有证据表明,血管 (尤其是它们的内皮细胞) 控制器官的生长、平衡和再生。在本期Nature上发表的两篇论文中,Ralf Adams及同事证明,骨头血管含有专门支持骨成熟和再生的内皮细胞。Anjali Kusumbe等人在小鼠骨骼系统内识别出一个在介导骨生长中起关键作用的毛细血管亚型。这些血管

Read More

论文摘要 CD4 T细胞(携带能够识别被病毒感染的细胞表面上的CD4抗原的受体的辅助T细胞)的丧失是艾滋病发病的根源。在这项研究中,Warner Greene等人识别出静止的淋巴CD4 T细胞在HIV感染过程中被耗尽的机制。利用保持了天然淋巴环境的人淋巴组织的体外培养,本文作者发现,失败的病毒复制触发

Read More