Abstract
An explosion of sequence information in the genomics era has thrown up thousands of protein sequences without functional assignment. Though our ability to predict function based on sequence alone is improving steadily, we still have a long way to go. Proteins with common evolutionary origins carry telling sequence signatures, which ought to reveal their biological roles. These sequence signatures have allowed us to classify proteins into families with similar structures, and possibly, functions. Yet, evolution is a perpetual tinkerer, and hence, sequence signatures alone have proved inadequate in understanding the physiological activities of proteins. One such enigmatic family of enzymes is the NUDIX ( nu cleoside di phosphate linked to a moiety X ) hydrolase family that has over 80000 members from all branches of the tree of life. Though MutT, the founding member of this family, was identified in 1954, we are only now beginning to understand the diversity of substrates and biological roles that these enzymes demonstrate. In a recent article by Cordeiro et al. in Bioscience Reports [Biosci. Rep. (2019)], two members of this protein family from the human pathogen Trypanosoma brucei were deorphanized as being polyphosphate hydrolases. The authors show that of the five NUDIX hydrolases coded by the T. brucei genomes, TbNH2 and TbNH4, show in vitro hydrolytic activity against inorganic polyphosphate. Through classical biochemistry and immunostaining microscopy, differences in their substrate specificities and sub-cellular localization were revealed. These new data provide a compelling direction to the study of Trypanosome stress biology as well as our understanding of the NUDIX enzyme family.