Uracil DNA glycosylases (UDGs) are important DNA repair enzymes that excise uracil from DNA, yielding an abasic site. Recently, UdgX, an unconventional UDG with extremely tight binding to DNA containing uracil, was discovered. The structure of UdgX from Mycobacterium smegmatis in complex with DNA shows an overall similarity to that of family 4 UDGs except for a protruding loop at the entrance of the uracil-binding pocket. Surprisingly, H109 in the loop was found to make a covalent bond to the abasic site to form a stable intermediate, while the excised uracil remained in the pocket of the active site. H109 functions as a nucleophile to attack the oxocarbenium ion, substituting for the catalytic water molecule found in other UDGs. To our knowledge, this change from a catalytic water attack to a direct nucleophilic attack by the histidine residue is unprecedented. UdgX utilizes a unique mechanism of protecting cytotoxic abasic sites from exposure to the cellular environment.

尿嘧啶DNA糖基化酶（UDG）是重要的DNA修复酶，可从DNA中切除尿嘧啶，产生无碱基位点。最近，发现了UdgX，这是一种非常规的UDG，与含有尿嘧啶的DNA具有极强的结合力。耻垢分枝杆菌UdgX的结构与DNA结合的蛋白显示出与4族UDG的总体相似性，只是在尿嘧啶结合口袋的入口处有一个突出的环。令人惊讶地，发现环中的H109与无碱基位点形成共价键以形成稳定的中间体，而切除的尿嘧啶保留在活性位点的口袋中。H109充当亲核试剂攻击氧碳鎓离子，取代了其他UDG中发现的催化水分子。据我们所知，这种由组氨酸残基从催化水攻击到直接亲核攻击的变化是前所未有的。UdgX利用独特的机制来保护细胞毒性无碱基位点，使其不暴露于细胞环境。