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Human metastasis regulator protein H-prune is a short-chain exopolyphosphatase.
- Source :
-
Biochemistry [Biochemistry] 2008 Sep 09; Vol. 47 (36), pp. 9707-13. Date of Electronic Publication: 2008 Aug 14. - Publication Year :
- 2008
-
Abstract
- The DHH superfamily human protein h-prune, a binding partner of the metastasis suppressor nm23-H1, is frequently overexpressed in metastatic cancers. From an evolutionary perspective, h-prune is very close to eukaryotic exopolyphosphatases. Here, we show for the first time that h-prune efficiently hydrolyzes short-chain polyphosphates (k cat of 3-40 s (-1)), including inorganic tripoly- and tetrapolyphosphates and nucleoside 5'-tetraphosphates. Long-chain inorganic polyphosphates (>or=25 phosphate residues) are converted more slowly, whereas pyrophosphate and nucleoside triphosphates are not hydrolyzed. The reaction requires a divalent metal cofactor, such as Mg (2+), Co (2+), or Mn (2+), which activates both the enzyme and substrate. Notably, the exopolyphosphatase activity of h-prune is suppressed by nm23-H1, long-chain polyphosphates and pyrophosphate, which may be potential physiological regulators. Nucleoside triphosphates, diadenosine hexaphosphate, cAMP, and dipyridamole (inhibitor of phosphodiesterase) do not affect this activity. Mutation of seven single residues corresponding to those found in the active site of yeast exopolyphosphatase led to a severe decrease in h-prune activity, whereas one variant enzyme exhibited enhanced activity. Our results collectively suggest that prune is the missing exopolyphosphatase in animals and support the hypothesis that the metastatic effects of h-prune are modulated by inorganic polyphosphates, which are increasingly recognized as critical regulators in cells.
- Subjects :
- Acid Anhydride Hydrolases genetics
Animals
Coenzymes genetics
Coenzymes metabolism
Gene Expression Regulation, Enzymologic genetics
Gene Expression Regulation, Neoplastic genetics
Humans
Inorganic Pyrophosphatase genetics
Inorganic Pyrophosphatase metabolism
Metals metabolism
Mutation
NM23 Nucleoside Diphosphate Kinases genetics
Neoplasm Proteins genetics
Neoplasms genetics
Acid Anhydride Hydrolases metabolism
NM23 Nucleoside Diphosphate Kinases metabolism
Neoplasm Proteins metabolism
Neoplasms enzymology
Polyphosphates metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 47
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18700747
- Full Text :
- https://doi.org/10.1021/bi8010847