Key Laboratory of Desert and Desertification, Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences, Lanzhou, Gansu, China.
Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Lanzhou, Gansu, China.
Nucleic Acids Res. 2022 Jul 8;50(12):7084-7096. doi: 10.1093/nar/gkac502.
We report the discovery and functional characterization of a new bacterial tRNA species. The tRNA-Asp-AUC, from a fast-growing desert streptomycete, decodes GAU codons. In the absence of queuosine tRNA anticodon modification in streptomycetes, the new tRNA circumvents inefficient wobble base-pairing during translation. The tRNA, which is constitutively expressed, greatly enhances synthesis of 4 different antibiotics in the model mesophilic species Streptomyces coelicolor, including the product of a so-called cryptic pathway, and increases yields of medically-important antibiotics in other species. This can be rationalised due to increased expression of both pleiotropic and pathway-specific transcriptional activators of antibiotic biosynthesis whose genes generally possess one or more GAT codons; the frequency of this codon in these gene sets is significantly higher than the average for streptomycete genes. In addition, the tRNA enhances production of cobalamin, a precursor of S-adenosyl methionine, itself an essential cofactor for synthesis of many antibiotics. The results establish a new paradigm of inefficient wobble base-pairing involving GAU codons as an evolved strategy to regulate gene expression and, in particular, antibiotic biosynthesis. Circumventing this by expression of the new cognate tRNA offers a generic strategy to increase antibiotic yields and to expand the repertoire of much-needed new bioactive metabolites produced by these valuable bacteria.
我们报告了一种新型细菌 tRNA 的发现和功能特征。该 tRNA-Asp-AUC 来自一种快速生长的沙漠链霉菌，可解码 GAU 密码子。在链霉菌中不存在 Queuosine tRNA 反密码子修饰的情况下，新型 tRNA 可避免在翻译过程中出现低效的摆动碱基配对。这种组成型表达的 tRNA 极大地增强了模式嗜热物种变铅青链霉菌中 4 种不同抗生素的合成，包括所谓的隐匿途径的产物，并提高了其他物种中具有医学重要性的抗生素的产量。这可以通过增加多效性和途径特异性抗生素生物合成转录激活因子的表达来合理化，这些转录激活因子的基因通常具有一个或多个 GAT 密码子；这些基因集中的这个密码子的频率明显高于链霉菌基因的平均频率。此外，该 tRNA 还增强了钴胺素（S-腺苷甲硫氨酸的前体）的产生，而 S-腺苷甲硫氨酸本身是许多抗生素合成所必需的辅因子。这些结果建立了一个新的无效摆动碱基配对范例，涉及 GAU 密码子，作为一种进化策略来调节基因表达，特别是抗生素生物合成。通过表达新型同源 tRNA 来规避这种情况，为提高抗生素产量和扩大这些有价值细菌产生的急需新型生物活性代谢物的 repertoire 提供了一种通用策略。
