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.
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DOI：
10.1002/anie.202009007
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发表时间：
2020-12-14
期刊：
影响因子：
--
通讯作者：
Challis GL
中科院分区：
文献类型：
--
作者：
Nakou IT;Jenner M;Dashti Y;Romero-Canelón I;Masschelein J;Mahenthiralingam E;Challis GL
在唐菖蒲伯克霍尔德菌BCC 0238和BCC 1622的基因组中鉴定出编码隐蔽的反式酰基转移酶聚酮合酶（PKS）的基因簇，这两种菌均分离自囊性纤维化患者的肺部。生物信息学分析表明，PKS组装的戊二酰亚胺类抗生素，迄今为止只从链霉菌属物种分离的新成员。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。基因组挖掘使得能够发现唐菖蒲抑制素，一种来自囊性纤维化相关细菌唐菖蒲伯克霍尔德氏菌的新型戊二酰亚胺抗生素。Gladiostatin含有一种不寻常的2-酰基-3-羟基-4-甲基丁烯酰亚胺，并对人类癌细胞表现出有希望的活性。负责其生物合成的聚酮合酶采用一种新的链释放机制，导致形成磷酸化的丁烯二酰亚胺中间体。
A gene cluster encoding a cryptic trans‐acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 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 from Streptomyces species. 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. Genome mining enabled the discovery of gladiostatin, a novel glutarimide antibiotic from the cystic fibrosis associated bacterium Burkholderia gladioli. Gladiostatin contains an unusual 2‐acyl‐3‐hydroxy‐4‐methylbutenolide and exhibits promising activity against human cancer cells. The polyketide synthase responsible for its biosynthesis employs a novel mechanism for chain release, resulting in formation of a phosphorylated butenolide intermediate.
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伯克霍尔德氏菌基因组对非核糖体肽合成酶的挖掘揭示了新型铁载体和脂肽合成的巨大潜力。
影响因子：
3.4
作者：
Esmaeel Q;Pupin M;Kieu NP;Chataigné G;Béchet M;Deravel J;Krier F;Höfte M;Jacques P;Leclère V
通讯作者：
Leclère V
DOI：
10.1073/pnas.0805530105
发表时间：
2008-11-11
影响因子：
11.1
作者：
Corre, Christophe;Song, Lijiang;Challis, Gregory L.
通讯作者：
Challis, Gregory L.
影响因子：
4.8
作者：
Lim, Si-Kyu;Ju, Jianhua;Shen, Ben
通讯作者：
Shen, Ben
DOI：
10.1002/anie.202009110
发表时间：
2020-11-23
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Dashti Y;Nakou IT;Mullins AJ;Webster G;Jian X;Mahenthiralingam E;Challis GL
通讯作者：
Challis GL
影响因子：
1.1
作者：
ALLEN, MS;BECKER, AM;RICKARDS, RW
通讯作者：
RICKARDS, RW