Kage Hirokazu, Kreutzer Martin F, Wackler Barbara, Hoffmeister Dirk, Nett Markus
Junior Research Group Secondary Metabolism of Predatory Bacteria, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Beutenbergstrasse 11a, 07745 Jena, Germany.
Chem Biol. 2013 Jun 20;20(6):764-71. doi: 10.1016/j.chembiol.2013.04.010.
Micacocidin is a thiazoline-containing natural product from the bacterium Ralstonia solanacearum that shows significant activity against Mycoplasma pneumoniae. The presence of a pentylphenol moiety distinguishes micacocidin from the structurally related siderophore yersiniabactin, and this residue also contributes to the potent antimycoplasma effects. The biosynthesis of the pentylphenol moiety, as deduced from bioinformatic analysis and stable isotope feeding experiments, involves an iterative type I polyketide synthase (iPKS), which generates a linear tetraketide intermediate from acyl carrier protein-tethered hexanoic acid by three consecutive, decarboxylative Claisen condensations with malonyl-coenzyme A. The final conversion into 6-pentylsalicylic acid depends on a ketoreductase domain within the iPKS, as demonstrated by heterologous expression in E. coli and subsequent site-directed mutagenesis experiments. Our results unveil the early steps in micacocidin biosynthesis and illuminate a bacterial enzyme that functionally resembles fungal polyketide synthases.
米卡考西定是一种来自青枯雷尔氏菌的含噻唑啉的天然产物，对肺炎支原体具有显著活性。戊基苯酚部分的存在使米卡考西定与结构相关的铁载体耶尔森菌素有所区别，并且该残基也有助于其强大的抗支原体作用。从生物信息学分析和稳定同位素喂养实验推断，戊基苯酚部分的生物合成涉及一种迭代型I聚酮合酶（iPKS），它通过与丙二酰辅酶A进行三次连续的脱羧克莱森缩合反应，从酰基载体蛋白连接的己酸生成线性四酮中间体。如在大肠杆菌中的异源表达及随后的定点诱变实验所示，最终转化为6-戊基水杨酸取决于iPKS内的一个酮还原酶结构域。我们的结果揭示了米卡考西定生物合成的早期步骤，并阐明了一种功能上类似于真菌聚酮合酶的细菌酶。
