Das Abhirup, Khosla Chaitan
Department of Chemistry, Stanford University, Stanford, California 94305-5025, USA
Acc Chem Res. 2009 May 19;42(5):631-9. doi: 10.1021/ar8002249.
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-beta-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.
天然产物主要由微生物和植物产生，可能是大分子且结构复杂的分子。这些分子由细胞装配线制造，其中酶以逐步方式构建分子。酶以模块化方式相互作用并协同工作以产生多样结构特征的方式一直是一个活跃的研究领域；这项工作为生物合成的精细细节提供了深入了解。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医学意义的物质——是由土壤细菌放线菌中的聚酮合酶（PKSs）合成的。对这些模块化酶系统进行的生物合成、酶学和结构生物学的协同研究产生了有趣的机制见解。一个称为最小PKS的核心模块负责合成一条高度反应性的、与蛋白质结合的聚β-酮硫酯链。在没有其他酶的情况下，最小PKS还催化链的起始和释放，产生各种多环芳香族化合物。在起始PKS模块存在的情况下，合成带有额外烷基、烯基或芳基引物单元的聚酮骨架，而一系列辅助PKS酶和修饰酶将最小PKS的产物转化为最终的天然产物。在本综述中，我们总结了通过最近对两种天然产物放线紫红素和R1128（A-D）的生物合成途径的研究而获得的关于这一PKS家族的知识。我们还讨论了这些基本见解对新型多环芳香族化合物工程生物合成的实际意义。有了对生物合成过程的更深入理解，我们可以在分子构建的各个阶段进行控制，从而在这个过程中引入非天然官能团。代谢工程为创造可能具有与其完全天然同类物相似性质的新型分子结构提供了许多新途径。
