Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
Integrative Medical Biology, Umeå University, 90187, Umeå, Sweden.
Angew Chem Int Ed Engl. 2019 Jan 28;58(5):1417-1421. doi: 10.1002/anie.201812326. Epub 2018 Dec 27.
Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks like phenotype in HeLa cells. Furthermore, results from DNA cross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.
大肠杆菌素是一种由某些带有 pks 基因组岛的人类微生物群细菌产生的小分子。pks 细菌在真核细胞中诱导遗传毒性表型，并与结直肠癌的进展有关。大肠杆菌素以良性前药形式产生，在出口前，由产生菌通过酶促成熟为其活性形式。尽管大肠杆菌素的完整结构尚未确定，但已描述了关键的结构特征，包括一个亲电环丙烷基序，据信该基序可使 DNA 烷基化。为了研究假定的“弹头”和前药策略对遗传毒性的影响，制备了一系列光不稳定的大肠杆菌素探针，在照射后在 HeLa 细胞中诱导出 pks 样表型。此外，DNA 交联和点击类似物的成像研究结果证实了这样一种假设，即大肠杆菌素通过直接靶向 DNA 来发挥其遗传毒性作用。
