Most of the proteins carrying the 23-residue MutT-related sequence are capable 
of hydrolyzing compounds with a general structure of nucleoside diphosphate 
linked to another moiety X and are called the Nudix hydrolases. Among the 22 
human Nudix proteins (identified by the sequence signature), some remain 
uncharacterized as enzymes without a defined substrate. Here, we reveal that the 
NUDT18 protein, whose substrate was unknown, can degrade 
8-oxo-7,8-dihydroguanine (8-oxo-Gua)-containing nucleoside diphosphates to the 
monophosphates. Because this enzyme is closely related to MTH1 (NUDT1) and MTH2 
(NUDT15), we propose that it should be named MTH3. Although these three human 
proteins resemble each other in their sequences, their substrate specificities 
differ considerably. MTH1 cleaves 8-oxo-dGTP but not 8-oxo-dGDP, whereas MTH2 
can degrade both 8-oxo-dGTP and 8-oxo-dGDP, although the intrinsic enzyme 
activity of MTH2 is considerably lower than that of MTH1. On the other hand, 
MTH3 is specifically active against 8-oxo-dGDP and hardly cleaves 8-oxo-dGTP. 
Other types of oxidized nucleoside diphosphates, 2-hydroxy-dADP and 
8-hydroxy-dADP, were also hydrolyzed by MTH3. Another notable feature of the 
MTH3 enzyme is its action toward the ribonucleotide counterpart. MTH3 can 
degrade 8-oxo-GDP as efficiently as 8-oxo-dGDP, which is in contrast to the 
finding that MTH1 and MTH2 show a limited activity against the ribonucleotide 
counterpart, 8-oxo-GTP. These three enzymes may function together to help 
maintain the high fidelity of DNA replication and transcription under oxidative 
stress.