HHMI, Massachusetts General Hospital, Boston, MA 02114.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
Proc Natl Acad Sci U S A. 2022 Feb 15;119(7). doi: 10.1073/pnas.2116840119.
Aminoacylated transfer RNAs, which harbor a covalent linkage between amino acids and RNA, are a universally conserved feature of life. Because they are essential substrates for ribosomal translation, aminoacylated oligonucleotides must have been present in the RNA world prior to the evolution of the ribosome. One possibility we are exploring is that the aminoacyl ester linkage served another function before being recruited for ribosomal protein synthesis. The nonenzymatic assembly of ribozymes from short RNA oligomers under realistic conditions remains a key challenge in demonstrating a plausible pathway from prebiotic chemistry to the RNA world. Here, we show that aminoacylated RNAs can undergo template-directed assembly into chimeric amino acid-RNA polymers that are active ribozymes. We demonstrate that such chimeric polymers can retain the enzymatic function of their all-RNA counterparts by generating chimeric hammerhead, RNA ligase, and aminoacyl transferase ribozymes. Amino acids with diverse side chains form linkages that are well tolerated within the RNA backbone and, in the case of an aminoacyl transferase, even in its catalytic center, potentially bringing novel functionalities to ribozyme catalysis. Our work suggests that aminoacylation chemistry may have played a role in primordial ribozyme assembly. Increasing the efficiency of this process provides an evolutionary rationale for the emergence of sequence and amino acid-specific aminoacyl-RNA synthetase ribozymes, which could then have generated the substrates for ribosomal protein synthesis.
氨酰化转移 RNA 是一类在氨基酸与 RNA 间形成共价键的分子，是生命普遍存在的特征。由于氨酰化转移 RNA 是核糖体翻译的必需底物，因此在核糖体出现之前，氨酰化寡核苷酸必定存在于 RNA 世界中。我们正在探索的一种可能性是，在被招募用于核糖体蛋白合成之前，氨酰酯键可能具有另一种功能。在证明从前生物化学到 RNA 世界的可行途径时，在真实条件下由短 RNA 寡聚物非酶组装核酶仍然是一个关键挑战。在这里，我们表明氨酰化 RNA 可以在模板指导下组装成具有活性的核酶的混合氨酰 RNA 聚合物。我们证明，这些混合聚合物可以通过生成混合锤头、RNA 连接酶和氨酰转移酶核酶来保留其所有 RNA 对应物的酶功能。具有不同侧链的氨基酸形成的键在 RNA 骨架中具有很好的耐受性，在氨酰转移酶的情况下，甚至在其催化中心也具有很好的耐受性，这可能为核酶催化带来新的功能。我们的工作表明，氨酰化化学可能在原始核酶组装中发挥了作用。提高这一过程的效率为序列和氨基酸特异性氨酰-RNA 合成酶核酶的出现提供了进化上的合理性，这些核酶随后可以生成核糖体蛋白合成的底物。
