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J Biol Chem, Vol. 274, Issue 31, 21735-21740, July 30, 1999

The Diadenosine Hexaphosphate Hydrolases from Schizosaccharomyces pombe and Saccharomyces cerevisiae Are Homologues of the Human Diphosphoinositol Polyphosphate Phosphohydrolase
OVERLAPPING SUBSTRATE SPECIFICITIES IN A MutT-TYPE PROTEIN

Stephen T. Safrany, Stephen W. Ingram^§, Jared L. Cartwright^¶, J. R. Falck, Alexander G. McLennan^¶, Larry D. Barnes^§, and Stephen B. Shears

From the  Inositide Signaling Group, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, the ^§ Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78284-7760, the ^¶ School of Biological Sciences, Life Sciences Building, University of Liverpool, Liverpool L69 7ZB, United Kingdom, and the  Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9038

Aps1 from Schizosaccharomyces pombe (Ingram, S. W., Stratemann, S. A., and Barnes, L. D. (1999) Biochemistry 38, 3649-3655) and YOR163w from Saccharomyces cerevisiae (Cartwright, J. L., and McLennan, A. G. (1999) J. Biol. Chem. 274, 8604-8610) have both previously been characterized as MutT family hydrolases with high specificity for diadenosine hexa- and pentaphosphates (Ap₆A and Ap₅A). Using purified recombinant preparations of these enzymes, we have now discovered that they have an important additional function, namely, the efficient hydrolysis of diphosphorylated inositol polyphosphates. This overlapping specificity of an enzyme for two completely different classes of substrate is not only of enzymological significance, but in addition, this finding provides important new information pertinent to the structure, function, and evolution of the MutT motif. Moreover, we report that the human protein previously characterized as a diphosphorylated inositol phosphate phosphohydrolase represents the first example, in any animal, of an enzyme that degrades Ap₆A and Ap₅A, in preference to other diadenosine polyphosphates. The emergence of Ap₆A and Ap₅A as extracellular effectors and intracellular ion-channel ligands points not only to diphosphorylated inositol phosphate phosphohydrolase as a candidate for regulating signaling by diadenosine polyphosphates, but also suggests that diphosphorylated inositol phosphates may competitively inhibit this process.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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