Biosynthesis of aromatic polyketides in bacteria.
Biosynthesis of aromatic polyketides in bacteria.
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DOI：
10.1021/ar8002249
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发表时间：
2009-05-19
影响因子：
18.3
通讯作者：
Khosla, Chaitan
中科院分区：
文献类型：
--
作者：
Das, Abhirup;Khosla, Chaitan
天然产物主要由微生物和植物产生，可能是结构复杂的大分子。这些分子是通过细胞装配线制造的，其中酶以逐步的方式构建分子。酶以模块化方式相互作用和协同工作以产生不同结构特征的方式一直是一个活跃的研究领域。这项工作提供了对生物合成细节的深入了解。许多多环芳香族天然产物，包括几种值得注意的抗癌、抗菌、抗真菌、抗病毒、抗寄生虫和其他具有药用价值的物质，都是由称为放线菌的土传细菌中的聚酮合酶 (PKS) 合成的。对这些模块化酶系统的协调一致的生物合成、酶学和结构生物学研究已经产生了有趣的机制见解。称为最小 PKS 的核心模块负责合成高反应性、蛋白质结合的聚-β-酮硫酯链。在没有其他酶的情况下，最小的 PKS 也会催化链的引发和释放，产生各种多环芳香族化合物。在存在起始 PKS 模块的情况下，合成带有额外烷基、烯基或芳基引物单元的聚酮化合物主链，而一系列辅助 PKS 酶和剪裁酶将最小 PKS 的产物转化为最终天然产物。在这篇文章中，我们总结了通过最近对两种天然产物放线菌素和 R1128 (A-D) 生物合成途径的研究所获得的有关 PKS 家族的知识。我们还讨论了这些基本见解对于新型多环芳香族化合物的工程生物合成的实际意义。随着对生物合成过程的深入了解，我们可以在分子构建的各个阶段进行控制，从而在该过程中引入非天然官能团。代谢工程师提供了许多新的途径来创建新颖的分子结构，这些结构可能具有类似于其完全自然的表亲的特性。
Natural products, produced chiefly by microorganisms and plants, can be large and structurally complex molecules. These molecules are manufactured by cellular assembly lines, in which enzymes construct the molecules in a stepwise fashion. The means by which enzymes interact and work together in a modular fashion to create diverse structural features has been an active area of research; the work has provided insight into the fine details of biosynthesis. A number of polycyclic aromatic natural products—including several noteworthy anticancer, antibacterial, antifungal, antiviral, antiparasitic, and other medicinally significant substances—are synthesized by polyketide synthases (PKSs) in soil-borne bacteria called actinomycetes. Concerted biosynthetic, enzymological, and structural biological investigations into these modular enzyme systems have yielded interesting mechanistic insights. A core module called the minimal PKS is responsible for synthesizing a highly reactive, protein-bound poly-β-ketothioester chain. In the absence of other enzymes, the minimal PKS also catalyzes chain initiation and release, yielding an assortment of polycyclic aromatic compounds. In the presence of an initiation PKS module, polyketide backbones bearing additional alkyl, alkenyl, or aryl primer units are synthesized, whereas a range of auxiliary PKS enzymes and tailoring enzymes convert the product of the minimal PKS into the final natural product. In this Account, we summarize the knowledge that has been gained regarding this family of PKSs through recent investigations into the biosynthetic pathways of two natural products, actinorhodin and R1128 (A–D). We also discuss the practical relevance of these fundamental insights for the engineered biosynthesis of new polycyclic aromatic compounds. With a deeper understanding of the biosynthetic process in hand, we can assert control at various stages of molecular construction and thus introduce unnatural functional groups in the process. The metabolic engineer affords a number of new avenues for creating novel molecular structures that will likely have properties akin to their fully natural cousins.
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影响因子：
16.8
作者：
Keatinge-Clay, A;Maltby, DA;Stroud, RM
通讯作者：
Stroud, RM
影响因子：
3.5
作者：
BIBB, MJ;SHERMAN, DH;HOPWOOD, DA
通讯作者：
HOPWOOD, DA
影响因子：
2.9
作者：
Findlow, SC;Winsor, C;Crump, MP
通讯作者：
Crump, MP
DOI：
10.1073/pnas.0709223105
发表时间：
2008-04-08
影响因子：
11.1
作者：
Ames, Brian Douglas;Korman, Tyler Paz;Tsai, Shiou-Chuan
通讯作者：
Tsai, Shiou-Chuan
影响因子：
3.3
作者：
Lee, TS;Khosla, C;Tang, Y
通讯作者：
Tang, Y