Identification of the Biosynthetic Pathway for the Antibiotic Bicyclomycin,Biochemistry

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Identification of the Biosynthetic Pathway for the Antibiotic Bicyclomycin
Biochemistry ( IF 2.9 ) Pub Date : 2017-11-07 00:00:00 , DOI: 10.1021/acs.biochem.7b00943
Jon B. Patteson ₁ , Wenlong Cai ₁ , Rachel A. Johnson ₁ , Kevin C. Santa Maria ₁ , Bo Li ₁

Affiliation

Diketopiperazines (DKPs) make up a large group of natural products with diverse structures and biological activities. Bicyclomycin is a broad-spectrum DKP antibiotic with unique structure and function: it contains a highly oxidized bicyclic [4.2.2] ring and is the only known selective inhibitor of the bacterial transcription termination factor, Rho. Here, we identify the biosynthetic gene cluster for bicyclomycin containing six iron-dependent oxidases. We demonstrate that the DKP core is made by a tRNA-dependent cyclodipeptide synthase, and hydroxylations on two unactivated sp³ carbons are performed by two mononuclear iron, α-ketoglutarate-dependent hydroxylases. Using bioinformatics, we also identify a homologous gene cluster prevalent in a human pathogen Pseudomonas aeruginosa. We detect bicyclomycin by overexpressing this gene cluster and establish P. aeruginosa as a new producer of bicyclomycin. Our work uncovers the biosynthetic pathway for bicyclomycin and sheds light on the intriguing oxidation chemistry that converts a simple DKP into a powerful antibiotic.

中文翻译：

抗生素双环霉素生物合成途径的鉴定

二酮哌嗪（DKP）构成了一大类具有不同结构和生物活性的天然产物。双环霉素是一种具有独特结构和功能的广谱DKP抗生素：它含有高度氧化的双环[4.2.2]环，并且是细菌转录终止因子Rho的唯一已知选择性抑制剂。在这里，我们确定了含有六个铁依赖性氧化酶的双环霉素的生物合成基因簇。我们证明了DKP核心是由tRNA依赖性环二肽合酶制成的，两个未激活的sp ³碳上的羟基化作用是由两个单核铁，α-酮戊二酸依赖性羟化酶进行的。使用生物信息学，我们还鉴定了人类病原体铜绿假单胞菌中普遍存在的同源基因簇。我们通过过表达该基因簇检测双环霉素，并建立铜绿假单胞菌作为双环霉素的新生产者。我们的工作揭示了双环霉素的生物合成途径，并揭示了将简单的DKP转化为强大的抗生素的有趣的氧化化学过程。

更新日期：2017-11-08

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