Type III Polyketide Synthases: Structure and Mechanism

一种新的聚酮组装机制已经在细菌中出现，用于生物合成小芳香残基，这些残基在越来越多的生物活性天然产物中起着重要的结构元件的作用。这些小的芳香聚酮是由同型二聚体（III型）聚酮合成酶（PKSs）合成的，这些聚酮合成酶在系统发育和生化上与无处不在的植物PKSs（如查尔酮合成酶）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，以及更复杂的抗菌和抗肿瘤天然产物如万古霉素、萘酚、海洋酮和肯多霉素的关键成分的形成。虽然III型PKSs结构简单，但它们在机制上可以说是最复杂的PKSs，因为在它们的同二聚体结构中包含了启动分子识别和装载、丙二烯基-辅酶a脱羧和聚酮链延伸以及最终的多种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可以使用各种复杂的方法进行研究，包括异种生物合成，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。虽然对相关植物酶的分析已经相当成熟，但对细菌对应酶的研究才刚刚开始，可以期望获得关于这些简单凝聚酶的新颖，有趣和潜在重要的信息。此外，对细菌III型PKSs的机制和结构的理解可能与模块化I型和迭代型II型细菌PKSs的生产性再造有关。随着第一个细菌PKS的高分辨率三维晶体结构——来自Streptomyces colicolor A3(2)的THN合成酶（THN synthase）的接近掌握，对这一新的细菌PKS亚类进行全面的结构和机制分析的阶段已经奠定。研究将扩展到其他细菌III型PKSs，包括那些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的生物合成的细菌。

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.