氨基酰tRNA合成酶的经典与非经典酶活性

氨基酰tRNA合成酶（aminoacyl-tRNA synthetases,aaRS）家族的经典功能是催化氨基酸与对应tRNA结合，形成氨基酰tRNA，参与蛋白质合成。aaRS在进化过程中不断增加与氨基酰化功能无关的新结构域，其亚细胞器定位也受到营养、压力信号、参与调控血管新生和炎症反应等内外部信号调控，且不同aaRS的突变导致不同人类疾病，提示aaRS具有信号传导功能，但缺少具体的生化机制。最新发现aaRS具有氨基酰转移酶活性。一种氨基酸可以被其对应的aaRS活化成氨基酰AMP，氨基酰AMP可以修饰与该aaRS相互作用蛋白质的赖氨酸，传递该氨基酸的丰度及结构信息，调控细胞信号网络。aaRS新功能的发现和研究，为解释aaRS的生理病理重要性提供新的方向。本文综述aaRS的进化及非经典功能，讨论aaRS氨基酰转移酶活性在细胞信号传导及其与疾病的相关性，也包括药物开发潜力。

The Canonical and Noncanonical Functions of Aminoacyl-tRNA Synthetases

The canonical functions of aminoacyl-tRNA synthetases (aaRS) are charging amino acids to their cognate tRNAs to ensure the precise protein synthesis. Over the course of evolution, aaRS progressively incorporated domains and motifs that have no essential connections to tRNA charging but play roles in cell signaling. These include mediating protein-protein interaction, protein subcellular localization and sensing and transmitting metabolites signals. Deregulated noncanonical aaRS functions are associated with array of human diseases. These all suggest that aaRS play roles beyond their tRNA charging activity, however, the underlying biochemical mechanisms remain to be elucidated. Recent studies revealed that aaRS have aminoacyl transferase activities. An amino acid can be specifically recognized and activated into aminoacyl-AMP by its cognate aaRS, and the formed aminoacyl-AMP in aaRS can modify lysines in proteins that physically interact with this aaRS. This aminoacylation senses and transmits amino acids abundance and side chain information into cell signaling network, provides opportunities to understand why additional domains are acquired by aaRS during evolution and how mutations in an aaRS causes specific human diseases. This review summarizes the noncanonical functions of aaRS and discusses how aaRS mutations may be linked to diseases.