Department of Pharmacology, University of California, San Diego, California, USA.
Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, Evry, France.
mSystems. 2024 Oct 22;9(10):e0099224. doi: 10.1128/msystems.00992-24. Epub 2024 Sep 12.
Colibactin, a nonribosomal peptide/polyketide produced by , is a virulence factor and putative carcinogen that damages DNA by interstrand crosslinking (ICL). While the genes for colibactin biosynthesis have been identified, studies are needed to elucidate the mechanisms regulating colibactin production and activity. Here we perform untargeted metabolomics of coli cultures to identify L-tryptophan as a candidate repressor of colibactin activity. When is grown in a minimal medium supplemented with L-tryptophan ICL of plasmid DNA is reduced by >80%. L-tryptophan does not affect the transcription of genes but protects from copper toxicity and triggers the expression of genes to export copper to the periplasm where copper can directly inhibit the ClbP peptidase domain. Thus, L-tryptophan and copper interact and repress colibactin activity, potentially reducing its carcinogenic effects in the intestine.
Colibactin is a small molecule produced by + that damages DNA, leading to oncogenic mutations in human genomes. Colibactin-producing (+) cells promote tumorigenesis in mouse models of colorectal cancer (CRC) and are elevated in abundance in CRC patient biopsies, making it important to identify the regulatory systems governing colibactin production. Here, we apply a systems biology approach to explore metabolite repression of colibactin production in + . We identify L-tryptophan as a repressor of colibactin genotoxicity that stimulates the expression of genes to export copper to the periplasm where it can inhibit ClbP, the colibactin-activating peptidase. These results work toward an antibiotic-sparing, prophylactic strategy to inhibit colibactin genotoxicity and its tumorigenic effects in the intestine.
由 产生的非核糖体肽/聚酮化合物 colibactin 是一种毒力因子和潜在的致癌物质，通过链间交联（ICL）损伤 DNA。虽然 colibactin 生物合成的 基因已经被鉴定出来，但仍需要研究来阐明调节 colibactin 产生和活性的机制。在这里，我们对 coli 培养物进行非靶向代谢组学分析，以鉴定 L-色氨酸为 colibactin 活性的候选抑制剂。当 在补充 L-色氨酸的最小培养基中生长时，质粒 DNA 的 ICL 减少了>80%。L-色氨酸不影响 基因的转录，但能抵抗铜毒性，并触发基因表达，将铜输出到周质，在周质中，铜可以直接抑制 ClbP 肽酶结构域。因此，L-色氨酸和铜相互作用并抑制 colibactin 活性，可能降低其在肠道中的致癌作用。
Colibactin 是一种由 + 产生的小分子，可损伤 DNA，导致人类基因组中的致癌突变。产生 colibactin 的 +(+)细胞促进结直肠癌（CRC）小鼠模型中的肿瘤发生，并且在 CRC 患者活检中丰度升高，因此确定调节 colibactin 产生的调控系统非常重要。在这里，我们应用系统生物学方法来探索 + 中 colibactin 产生的代谢物抑制。我们确定 L-色氨酸是 colibactin 遗传毒性的抑制剂，它刺激基因表达，将铜输出到周质，在那里铜可以抑制 ClbP，即 colibactin 激活的肽酶。这些结果为抑制 colibactin 遗传毒性及其在肠道中的致瘤作用的抗生素节约、预防性策略提供了依据。
