Genomics-Driven Discovery of a Novel Glutarimide Antibiotic from Burkholderia gladioli Reveals an Unusual Polyketide Synthase Chain Release Mechanism
Genomics-Driven Discovery of a Novel Glutarimide Antibiotic from Burkholderia gladioli Reveals an Unusual Polyketide Synthase Chain Release Mechanism
复制标题
基因组学驱动的从剑兰伯克霍尔德氏菌中发现新型戊二酰亚胺抗生素揭示了不寻常的聚酮合酶链释放机制
DOI：
10.1002/ange.202009007
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发表时间：
2020
影响因子：
--
通讯作者：
Nakou I
中科院分区：
文献类型：
--
作者：
Nakou I
在唐菖蒲伯克霍尔德菌BCC 0238和BCC 1622的基因组中发现了一个编码隐蔽的反式酰基转移酶聚酮合酶（PKS）的基因簇，这两种细菌都是从囊性纤维化患者的肺部分离出来的。生物信息学分析表明，PKS组装的戊二酰亚胺类抗生素的新成员，迄今为止只从链霉菌属分离。一系列生长参数的筛选导致了对剑草抑素的鉴定，剑草抑素是PKS的代谢产物。NMR光谱分析显示，对几种人类癌细胞系具有有希望的活性并抑制肿瘤细胞迁移的海鞘抑制素除了含有戊二酰亚胺药效团外，还含有不寻常的2-酰基-4-羟基-3-甲基丁烯酰亚胺。在PKS的C-末端的AfsA-样结构域显示催化3-酮硫酯与二羟丙酮磷酸的缩合，因此表明它在聚酮链释放和丁烯二酸形成中起关键作用。
A gene cluster encoding a cryptic trans‐acyl transferase polyketide synthase (PKS) was identified in the genomes ofBurkholderia gladioliBCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated fromStreptomycesspecies. Screening of a range of growth parameters led to the identification of gladiostatin, the metabolic product of the PKS. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2‐acyl‐4‐hydroxy‐3‐methylbutenolide in addition to the glutarimide pharmacophore. An AfsA‐like domain at the C‐terminus of the PKS was shown to catalyze condensation of 3‐ketothioesters with dihydroxyacetone phosphate, thus indicating it plays a key role in polyketide chain release and butenolide formation.