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，用于生物合成作为越来越多生物活性天然产物的重要结构元素的小芳香族残基。这些小芳香族聚酮是由同源二聚体(III型)聚酮合成酶(PKS)合成的，这些PKS与查尔酮合成酶等普遍存在的植物PKS具有亲缘关系和生物化学关系。到目前为止，III型PKS已被证明参与了天然产物如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、萘蝶平、马利诺酮和肯德霉素的关键成分的形成。虽然III型PKS在结构上很简单，但可以说它们代表了最复杂的PKS，因为它们的同源二聚体结构中包含了启动分子识别和加载、丙二酰辅酶A脱羧基和聚酮链延伸所必需的催化机制，并最终实现了多种终止途径。它们简单的基因和蛋白质结构使它们可以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，以及原子分辨蛋白质X射线结晶学。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，有望获得关于这些简单缩合酶的新颖、有趣和潜在的重要信息。此外，对细菌III型PKSS的机制和结构的了解可能与模块化的I型和迭代的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的获得，来自天蓝色链霉菌A3(2)的THN合成酶即将到来，为全面分析这一新的细菌PKS亚类的结构和机制奠定了基础。研究将扩展到其他III型细菌PKS，包括那些参与临床上重要的糖肽万古霉素、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.