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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Nonorthologous replacement of lysyl-tRNA synthetase prevents addition of lysine analogues to the genetic code
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Nonorthologous replacement of lysyl-tRNA synthetase prevents addition of lysine analogues to the genetic code

机译：非直系置换赖氨酸-tRNA合成酶可防止向基因密码中添加赖氨酸类似物

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摘要

Insertion of lysine during protein synthesis depends on the enzyme lysyl-tRNA synthetase (LysRS), which exists in two unrelated forms, LysRS1 and LysRS2. LysRS1 has been found in most archaea and some bacteria, and LysRS2 has been found in eukarya, most bacteria, and a few archaea, but the two proteins are almost never found together in a single organism. Comparison of structures of LysRS1 and LysRS2 complexed with lysine suggested significant differences in their potential to bind lysine analogues with backbone replacements. One such naturally occurring compound, the metabolic intermediate S-(2-aminoethyl)-L-cysteine, is a bactericidal agent incorporated during protein synthesis via LysRS2. In vitro tests showed that S-(2-aminoethyl)-L-cysteine is a poor substrate for LysRS1, and that it inhibits LysRS1 200-fold less effectively than it inhibits LysRS2. In vivo inhibition by S-(2-aminoethyl)-L-cysteine was investigated by replacing the endogenous LysRS2 of Bacillus subtilis with LysRS1 from the Lyme disease pathogen Borrelia burgdorferi. B. subtilis strains producing LysRS1 alone were relatively insensitive to growth inhibition by S-(2-aminoeth-yl)-L-cysteine, whereas a WT strain or merodiploid strains producing both LysRS1 and LysRS2 showed significant growth inhibition under the same conditions. These growth effects arising from differences in amino acid recognition could contribute to the distribution of LysRS1 and LysRS2 in different organisms. More broadly, these data demonstrate how diversity of the aminoacyl-tRNA synthetases prevents infiltration of the genetic code by noncanonical amino acids, thereby providing a natural reservoir of potential antibiotic resistance.
机译：蛋白质合成过程中赖氨酸的插入取决于赖氨酸-tRNA合成酶（LysRS），它以两种不相关的形式存在，即LysRS1和LysRS2。在大多数古细菌和某些细菌中发现了LysRS1，而在真核生物，大多数细菌和一些古细菌中发现了LysRS2，但是在单个生物中几乎从未同时发现这两种蛋白质。与赖氨酸复合的LysRS1和LysRS2的结构比较表明，它们结合赖氨酸类似物与骨架替代物的潜力存在显着差异。一种这样的天然存在的化合物，代谢中间体S-（2-氨基乙基）-L-半胱氨酸，是在通过LysRS2进行蛋白质合成过程中掺入的杀菌剂。体外测试表明，S-（2-氨基乙基）-L-半胱氨酸是LysRS1的较差底物，与LysRS2相比，它抑制LysRS1的效果要低200倍。通过用来自莱姆病病原体伯氏疏螺旋体的LysRS1替代枯草芽孢杆菌的内源性LysRS2，研究了S-（2-氨基乙基）-L-半胱氨酸的体内抑制作用。单独产生LysRS1的枯草芽孢杆菌菌株对S-（2-氨基乙基-基）-L-半胱氨酸的生长抑制相对不敏感，而同时产生LysRS1和LysRS2的WT菌株或类金属倍体菌株显示出显着的生长抑制。这些由于氨基酸识别差异而产生的生长效应可能有助于LysRS1和LysRS2在不同生物体中的分布。更广泛地讲，这些数据证明了氨酰基-tRNA合成酶的多样性如何防止非规范氨基酸对遗传密码的渗透，从而提供了潜在的抗生素耐药性的天然储备。

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