The NUDIX hydrolases exist in all branches of life and catalyze the hydrolysis of a wide range of phosphate substrates. So far, 24 NUDIX hydrolases genes have been identified in the human genome. NUDT1 (also called MTH1) is one of the most investigated NUDIX hydrolases, and is found to be involved in certain diseases. NUDT1 can degrade a variety of substrates, including 8-OH-(d)GTP, 8-OH-(d)ATP, and 2-OH-(d)ATP. Because 8-OH-(d)GDP is usually produced by cellular oxidative stress events and causes genome damage, NUDT1 has been supposed to help maintain nucleic acid integrity and prevent oxidative-stress-related diseases, such as Parkinson’s disease and cancers. Another NUDIX hydrolases NUDT5 was also considered to be involved in cancer due to its 8-OH-(d)GDP hydrolysis activity. Knockdown of NUDT5 can suppress the proliferation of Hela cells and T47D cells but it didn’t induce DNA oxidative lesions. Recent studies revealed another function of NUDT5: driving nuclear ATP synthesis, which may play an important role in breast cancer. Previously, NUDT5 has been found to catalyze 5′diphosphoribose (ADP-ribose, ADPR) hydrolysis into ribose-5-phosphate (R5P) and adenosine 5′-monophosphate (AMP). The presence of pyrophosphate, NUDT5-catalyzed ADPR hydrolysis can generate both AMP and ATP. Nuclear ATP is the energy source for fundamental biological processes, such as chromatin remodeling and transcriptional change. Hormones like estrogen and progestin can induce such processes which could be carcinogenic. NUDT5 was also found to be overexpressed in breast cancer patients and is correlated with a poorer prognosis and a higher risk of recurrence and metastasis. These findings revealed the important role NUDT5 played in the estrogen signaling pathway and that it is thus involved in the pathogenesis of breast cancer. It also suggested that inhibitors of NUDT5 could be used as new drugs for the disease. Here you have the crystal structure of human NUDT5 in complex with the competitive inhibitor ibrutinib (PDB code: 8RIY)