Nature: 打破教科书，生命体中不再局限于使用20种常见氨基酸构建蛋白质

英国科学家成功打破生命只能利用20种氨基酸的僵局！

据英国医学研究委员会分子生物学实验室（LMB）的研究团队在《自然》杂志报告，他们成功开发出一种有效的方法，可以诱导细菌将结构上不寻常的非常见氨基酸添加到蛋白质中。这一突破意味着，生命体中不再局限于使用20种常见氨基酸构建蛋白质。

长久以来，科学家一直在探索为什么生命体中只出现了这20种氨基酸，并试图使用其他氨基酸构建蛋白质。传统的生物学教科书告诉我们，地球上所有生命体的蛋白质都只由20种氨基酸构成。但现在，这一传统被成功打破了。

研究人员通过突变氨酰tRNA合成酶的基因，创造出数百万种可能与外来氨基酸结合的替代版本。随后，他们将这些酶插入大肠杆菌，观察核糖体是否能成功将这些非常见氨基酸添加到蛋白质中。目前已成功了4个非常见氨基酸的添加，为生物学领域带来了新的突破和希望。

蛋白质合成有两个关键步骤：转录和翻译。首先，短链的转运RNA（tRNA）将氨基酸运送到细胞的蛋白质组装器——核糖体中，每个tRNA都能编码特定的氨基酸，通过氨酰tRNA合成酶将氨基酸连接到合适的tRNA上。其次，携带着氨基酸的tRNA与包含所有遗传信息的信使RNA（mRNA）长链结合，完成遗传信息的复制。

苏黎世大学的化学家Alexandria Deliz Liang将蛋白质制造比作组装火车：首先必须装载火车车厢，然后将这些车厢连接在一起。为了生产新种类的蛋白质，研究人员必须让这两个步骤同时发挥作用。LMB的化学家Jason Chin补充道：“如果其中任何一个不起作用，系统就会失败。”

这一突破意味着，未来或许可以创造出更多种类的蛋白质，为生命科学领域带来了新的希望和可能性。这项突破性的研究成果有望为医药和生物工程领域带来革命性的变革，值得期待！

The genetic code of living cells has been reprogrammed to enable the site-specific incorporation of hundreds of non-canonical amino acids into proteins, and the encoded synthesis of non-canonical polymers and macrocyclic peptides and depsipeptides1,2,3. Current methods for engineering orthogonal aminoacyl-tRNA synthetases to acylate new monomers, as required for the expansion and reprogramming of the genetic code, rely on translational readouts and therefore require the monomers to be ribosomal substrates4,5,6. Orthogonal synthetases cannot be evolved to acylate orthogonal tRNAs with non-canonical monomers (ncMs) that are poor ribosomal substrates, and ribosomes cannot be evolved to polymerize ncMs that cannot be acylated onto orthogonal tRNAs—this co-dependence creates an evolutionary deadlock that has essentially restricted the scope of translation in living cells to α-L-amino acids and closely related hydroxy acids. Here we break this deadlock by developing tRNA display, which enables direct, rapid and scalable selection for orthogonal synthetases that selectively acylate their cognate orthogonal tRNAs with ncMs in Escherichia coli, independent of whether the ncMs are ribosomal substrates. Using tRNA display, we directly select orthogonal synthetases that specifically acylate their cognate orthogonal tRNA with eight non-canonical amino acids and eight ncMs, including several β-amino acids, α,α-disubstituted-amino acids and β-hydroxy acids. We build on these advances to demonstrate the genetically encoded, site-specific cellular incorporation of β-amino acids and α,α-disubstituted amino acids into a protein, and thereby expand the chemical scope of the genetic code to new classes of monomers.

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