近日，美国莱斯大学Renata, Hans团队提出了实用生物催化硫代磷酸化的ATPγS回收策略。2026年7月15日，《自然》杂志发表了这一成果。

鉴于其优异的代谢稳定性，硫代磷酸酯基团被广泛视为天然磷酸酯类似物的有价值替代品。这一特性促使硫代磷酸酯和硫代磷酸酯类化合物被纳入多种治疗模式中，例如反义寡核苷酸和环二核苷酸类似物。在生物化学上，硫代磷酸酯可通过蛋白激酶与腺苷-5′-O-(3-硫代三磷酸)（ATPγS）的组合安装到蛋白质上，但该方法从未在其他底物类别上得到探索，且由于需要超化学计量的昂贵ATPγS，难以放大生产。

研究组报道了一种ATPγS循环策略的发明，该策略通过使用一种特殊设计的肌酸衍生物来周转激酶反应的副产物，从而规避了上述限制。所开发的方案显著提高了酶促硫代磷酸化的实用性，并与多种激酶相容。该策略的多功能性通过设计多酶级联反应得到了验证，成功合成了多种含硫代磷酸基团的小分子和大分子，包括核苷5′-单硫代磷酸酯、3′,5′-环状单硫代磷酸酯和硫代磷酸化寡肽。该研究结果为药物开发中涉及含硫代磷酸酯类化合物的新生物催化方法奠定了基础。

附：英文原文

Title: An ATPγS recycling strategy for practical biocatalytic thiophosphorylation

Author: Wu, Xiangyu, Fu, Yu, Renata, Hans

Issue&Volume: 2026-07-15

Abstract: In light of its superior metabolic stability, the thiophosphate motif is widely regarded as a valuable substitute for its native phosphate counterpart1–3. This property has led to the incorporation of thiophosphates and phosphorothioates in various therapeutic modalities, such as antisense oligonucleotides4,5 and cyclic dinucleotide analogs6. Biochemically, thiophosphates can be installed on proteins by combining protein kinases and adenosine-5′-O-(3-thio-triphosphate) (ATPγS)7, but the method has never been explored on additional substrate classes and is impractical to scale up because it requires superstoichiometric amounts of the expensive ATPγS. Here, we report the invention of an ATPγS recycling strategy, which circumvents these limitations through the use of a specially designed creatine derivative to turn over the kinase reaction byproduct. The developed protocol significantly improves the practicality of enzymatic thiophosphorylation and is compatible with many kinases. The versatility of the strategy is demonstrated in the design of multi-enzyme cascades to synthesize a diverse range of thiophosphate-containing small and macromolecules, including nucleoside 5′-monothiophosphates, 3′,5′-cyclic monophosphorothioates and thiophosphorylated oligopeptides. Our findings open the door for new biocatalytic approaches to thiophosphate-containing modalities in drug development endeavors.

DOI: 10.1038/s41586-026-10895-9

Source: https://www.nature.com/articles/s41586-026-10895-9

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html