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A key tyrosine substitution restricts nucleotide hydrolysis by the ectoenzyme NPP 5
Author(s) -
Gorelik Alexei,
Randriamihaja Antsa,
Illes Katalin,
Nagar Bhushan
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14266
Subject(s) - nucleotide , biochemistry , cyclic nucleotide phosphodiesterase , nad+ kinase , tyrosine , chemistry , enzyme , nicotinamide adenine dinucleotide , biology , phosphodiesterase , gene
The ecto‐nucleotide pyrophosphatase/phosphodiesterase ( NPP ) family of proteins mediates purinergic signaling by degrading extracellular nucleotides and also participates in phospholipid metabolism. NPP 5 ( ENPP 5 ) is the least characterized member of this group and its specific role is unknown. This enzyme does not display activity on certain nucleotides and on other typical NPP substrates. In order to gain insights into its function, we determined the crystal structure of human and murine NPP 5. Structural comparison with close homologs revealed a key phenylalanine to tyrosine substitution that prevents efficient hydrolysis of nucleotide diphosphates and triphosphates; reversal of this mutation enabled degradation of these molecules. Interestingly, NPP 5 is able to cleave nicotinamide adenine dinucleotide ( NAD ), suggesting a potential role of this enzyme in NAD ‐based neurotransmission. An NPP 5‐specific metal binding motif is found adjacent to the active site, although its significance is unclear. These findings expand our understanding of substrate specificity within the NPP family. Database Structural data are available in the Protein Data Bank under the accession numbers 5VEM , 5VEN , and 5VEO .