Type III Polyketide Synthases: Structure and Mechanism

在细菌中出现了一种新的聚酮组装机制，用于小芳香残基的生物合成，这些小芳香残基在越来越多的生物活性天然产物中充当重要的结构元件。 这些小的芳香族聚酮化合物由同源二聚体（III型）聚酮化合物脱氢酶（PKS）合成，所述PKS与普遍存在的植物PKS如查耳酮合酶在遗传学和生物化学上相关。 到目前为止，III型PKS已被证明负责天然产物如1，3，6，8-四羟基萘（THN）的生物合成以及更复杂的抗微生物和抗肿瘤天然产物如万古霉素、萘啶、marinone和肯多霉素的关键组分的形成。 虽然III型PKS在结构上是简单的，但它们在机理上可以说代表了最复杂的PKS，因为在它们的同二聚体结构中体现的是起始分子识别和装载、丙二酰辅酶A脱羧和聚酮化合物链延伸以及最终的多个终止途径所必需的催化机制。 它们简单的基因和蛋白质结构使它们能够使用各种复杂的方法进行研究，包括异源生物合成，体外和体内生化分析，酶工程的定向和随机方法，以及原子分辨率蛋白质X射线晶体学。 虽然相关的植物酶的分析是相当成熟的，对细菌对应物的研究才刚刚开始，可以预期产生新的，有趣的，和潜在的重要信息，这些简单的缩合酶。 此外，对细菌III型PKS的机制和结构的理解可能与模块化I型和迭代II型细菌PKS的生产性重组有关。 随着第一个细菌PKS的高分辨率三维晶体结构，来自天蓝色链霉菌A3的THN合酶（2），几乎在手，为细菌PKS的这个新亚类的全面结构和机制分析奠定了基础。 研究将扩展到其他细菌III型PKS，包括参与临床重要糖肽万古霉素、广谱抗生素2，4-二乙酰间苯三酚和抗肿瘤抗生素marinone生物合成的PKS。

A new mechanism of polyketide assembly has emerged in bacteria for the biosynthesis of small aromatic residues that serve as important structural elements in a growing number of biologically active natural products. These small aromatic polyketides are synthesized by homodimeric (type III) polyketide synthases (PKSs) that are phylogenetically and biochemically related to ubiquitous plant PKSs such as chalcone synthase. Thus far, type III PKSs have been shown to be responsible for the biosynthesis of natural products such as 1,3,6,8- tetrahydroxynaphthalene (THN) and the formation of key components of more complex antimicrobial and antitumor natural products such as vancomycin, naphterpin, marinone, and kendomycin. While type III PKSs are architecturally simple, they arguably represent the most sophisticated PKSs mechanistically since embodied within their homodimeric architecture is the catalytic machinery necessary for starter molecule recognition and loading, malonyl- CoA decarboxylation and polyketide chain extension, and ultimately, multiple pathways for termination. Their simple gene and protein architecture makes them amendable for study using a variety of sophisticated approaches including heterologous biosynthesis, in vitro and in vivo biochemical analysis, directed and random approaches towards enzyme engineering, and atomic resolution protein x-ray crystallography. Although the analysis of related plant enzymes is fairly mature, research on the bacterial counterparts is only beginning and can be expected to yield novel, interesting, and potentially important information on these simple condensing enzymes. Moreover, the mechanistic and structural understanding of bacterial type III PKSs is likely to be relevant for the productive reengineering of modular type I and iterative type II bacterial PKSs. With the high resolution three-dimensional crystal structure of the first bacterial PKS, THN synthase from Streptomyces coelicolor A3(2), nearly in hand, the stage is set for a comprehensive structural and mechanistic analysis of this new subclass of bacterial PKS. Studies will extend to other bacterial type III PKSs, including those involved in the biosynthesis of the clinically important glycopeptide vancomycin, the broad spectrum antibiotic 2,4- diacetylphloroglucinol, and the antitumor antibiotic marinone.