The main focus of my research is the structural biology analysis of the Nudix hydrolases. These hydrolases comprise a super-family of enzymes involved in the removal of toxic and metabolic intermediates from the cell. They are conserved across species and are characterized by the signature amino acid sequence GXXXXXEXXXXXXXREUXEEX2U, (U=Ile, Leu, Val). The enzymes catalyze the hydrolysis of compounds such as NADH, NTP, or ADP-ribose (ADPR) that consist of a nucleoside diphosphate linked to different moieties. More than 30 enzymes have been biochemicaly characterized so far; they are classified in at least 8 families and they all depend on a divalent cation for activity. Given the wide distribution of these enzymes and the physiological roles of their substrates, it is important to understand their mechanisms and their specificity, which will be essential for designing specific inhibitors.

Our work led to the first structural characterization of Nudix hydrolases of different families including the ADPRase, the CoA pyrophosphatase, GDP-mannose hydrolases and the dATPase families. The Nudix fold, the only common motif to all, is tailored for metal binding and different quaternary structure arrangements are used for substrate recognition.

Publications

Email: gabelli@jhmi.edu