Nudix hydrolase 5 (NUDT5)

Nudix hydrolase 5 (NUDT5) is an enzyme in the Nudix hydrolase family, primarily acting as an ADP-sugar pyrophosphatase that hydrolyzes ADP-ribose and related ADP-sugar molecules to generate nuclear ATP, which is essential for rapid chromatin remodeling, hormone-induced gene regulation, and cell proliferation. NUDT5 also maintains the integrity of the nucleotide pool by sanitizing oxidized nucleotides (such as 8-oxo-dGDP), although its physiological role in oxidative nucleotide sanitation is less prominent compared to its major function in ADP-ribose metabolism. NUDT5 has emerged as a potential therapeutic target, particularly in hormone-driven cancers such as breast cancer, where inhibition suppresses hormone-dependent gene regulation and cell proliferation by disrupting nuclear ATP synthesis. Recent genetic studies highlight its role in modulating thiopurine response in leukemia, proposing it as a pharmacogenetic determinant in chemotherapy. The protein is characterized structurally by typical Nudix motifs essential for its catalytic activity, engaging Mg2+ ions and key residues to hydrolyze substrates. NUDT5’s multifaceted involvement in nuclear energy metabolism, transcriptional regulation, and drug response underscore its clinical and biological significance, while making it a complex target for both biomarker and drug development.

Other names

ADP-sugar pyrophosphataseNUDIX5HSPC115Nudix motif 5hNUDT5hYSAH1YSA1H8-oxo-dGDP phosphatasenuclear ATP-synthesis protein NUDIX5nucleoside diphosphate-linked moiety X motif 5

Inhibition of nuclear ATP synthesis via blockade of ADP-ribose hydrolysis (e.g., chromatin remodeling inhibition by compounds like TH5427 in cancer cells); Modulation of thiopurine response through alteration of purine metabolism and nucleotide pool.