北京大学郭少军研究组揭示了铜单位点在BO₂上作为甲状腺过氧化物酶模拟碘酪氨酸偶联及药物评价。这一研究成果于2025年3月9日发表在国际顶尖学术期刊《科学通报》上。

本文设计并合成了一类以Cu-N₅为催化位点，BO₂为结合位点的三维催化中心SACs (BO₂/CuN₅C)，模拟TPO激活H₂O₂，促进酪氨酸碘化和偶联产生甲状腺激素。该研究组证明了制备的BO₂/CuN₅C不仅通过氢键相互作用为H₂O₂提供结合位点，而且还具有促进O-O异解过程的催化位点。具有TPO样催化中心的BO₂/CuN₅C与CuN₅C相比，分别能生产3,3 ''，5-三碘甲状腺原氨酸和D-甲状腺素，分别提高2.4倍和11.1倍。

此外，2-巯基-1-甲基咪唑和6-丙基-2-硫代酸抗甲状腺药物体外研究的评价符合欧洲甲状腺协会指南，可为临床用药提供指导，预防毒性反应。总的来说，这项工作开启了一种精确模拟天然酶活性位点的方法，用于氨基酸偶联和药物评估。

据介绍，在单原子催化剂（SACs）中设计模拟甲状腺过氧化物酶（TPO）功能的三维（3D）催化位点以实现碘酪氨酸偶联，尽管这对甲状腺激素的合成是非常理想的，但这是一个巨大的挑战。

附：英文原文

Title: Cu single sites on BO2 as thyroid peroxidase mimicking for iodotyrosine coupling and pharmaceutical assess

Author: Lei Jiao a, Xiaoquan Lu a c, Yanling Zhai a, Shaojun Guo b

Issue&Volume: 2025/03/09

Abstract: Designing three-dimensional (3D) catalytic sites in single-atom catalysts (SACs) that mimic thyroid peroxidase (TPO) function for achieving iodotyrosine coupling, although highly desirable for the synthesis of thyroid hormones, poses a great challenge. Herein, we design and synthesize a class of SACs with 3D catalytic centers composed of Cu-N₅ as catalytic sites and BO₂ as binding sites (BO₂/CuN₅C) for mimicking TPO in activating H₂O₂ to facilitate tyrosine iodination and conjugation for producing thyroid hormones. We demonstrate that the as-prepared BO₂/CuN₅C not only provides binding sites for H₂O₂ through hydrogen bond interactions but also possesses catalytic sites to promote an alternative O-O heterolysis process. BO₂/CuN₅C with TPO-like catalytic centers can produce 3,3’,5-triiodothyronine and D-thyroxine with 2.4-fold and 11.1-fold improvements relative to those of CuN₅C. Besides, the assessment of 2-mercapto-1-methylimidazole and 6-propyl-2-thiouracil in vitro investigations of antithyroid drugs corresponds well with the European Thyroid Association guidelines and therefore can provide clinical medication guidance to prevent toxic reactions. Overall, this work unlocks an approach to precisely simulate the natural enzyme active site for amino acid coupling and pharmaceutical assessment.

DOI: 10.1016/j.scib.2025.03.010

Source: https://www.sciencedirect.com/science/article/abs/pii/S2095927325002385