Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases. An expanding Nudt family

• Published in: The Journal of biological chemistry Vol. 275; no. 17; pp. 12730 - 12736
• Main Authors: Caffrey, J J, Safrany, S T, Yang, X, Shears, S B
• Format: Journal Article
• Language: English
• Published: United States 28.04.2000
• Subjects: Acid Anhydride Hydrolases - chemistry; Acid Anhydride Hydrolases - metabolism; Amino Acid Sequence; Animals; Blotting, Northern; Blotting, Western; Catalysis; Chromatography, High Pressure Liquid; diphosphoinositol-polyphosphate phosphohydrolases; Evolution, Molecular; hDIPP1 protein; hDIPP2^a protein; hDIPP2^b protein; Humans; Mice; Models, Biological; Molecular Sequence Data; Multigene Family; Myocardium - metabolism; Polymerase Chain Reaction; Protein Isoforms; Rats; Recombinant Proteins - metabolism; RNA, Messenger - metabolism; Sequence Homology, Amino Acid; Tissue Distribution
• ISSN: 0021-9258
• DOI: 10.1074/jbc.275.17.12730

The turnover of the "high energy" diphosphoinositol polyphosphates by Ca(2+)- and cyclic nucleotide-modulated enzymes is considered a regulatory, molecular switching activity. Target processes may include intracellular trafficking. Following our earlier identification of a prototype human diphosphoinositol-polyphosphate phosphohydrolase (hDIPP1), we now describe new 21-kDa human isoforms, hDIPP2alpha and hDIPP2beta, distinguished from each other solely by hDIPP2beta possessing one additional amino acid (Gln(86)). Candidate DIPP2alpha and DIPP2beta homologues in rat and mouse were also identified. The rank order for catalytic activity is hDIPP1 > hDIPP2alpha > hDIPP2beta. Differential expression of hDIPP isoforms may provide flexibility in response times of the molecular switches. The 76% identity between hDIPP1 and the hDIPP2s includes conservation of an emerging signature sequence, namely, a Nudt (MutT) motif with a GX(2)GX(6)G carboxy extension. Northern and Western analyses indicate expression of hDIPP2s is broad but atypically controlled; these proteins are translated from multiple mRNAs that differ in the length of the 3'-untranslated region because of utilization of an array of alternative (canonical and noncanonical) polyadenylation signals. Thus, cells can recruit sophisticated molecular processes to regulate diphosphoinositol polyphosphate turnover.