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Understanding inositol pyrophosphate metabolism and function: Kinetic characterization of the DIPPs
Authors:Rajagopal S Kilari  Jeremy D Weaver  Stephen B Shears  Stephen T Safrany
Institution:1. Department of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wulfruna Street, Wolverhampton WV11LY, UK;2. Inositide Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, PO Box 12233, NC 27709, USA
Abstract:We illuminate the metabolism and the cell-signaling activities of inositol pyrophosphates, by showing that regulation of yeast cyclin-kinase by 1-InsP7 is not conserved for mammalian CDK5, and by kinetically characterizing Ddp1p/DIPP-mediated dephosphorylation of 1-InsP7, 5-InsP7 and InsP8. Each phosphatase exhibited similar Km values for every substrate (range: 35–148 nM). The rank order of kcat values (1-InsP7 > 5-InsP7 = InsP8) was identical for each enzyme, although DIPP1 was 10- to 60-fold more active than DIPP2α/β and DIPP3α/β. We demonstrate InsP8 dephosphorylation preferentially progresses through 1-InsP7. Conversely, we conclude that the more metabolically and functionally significant steady-state route of InsP8 synthesis proceeds via 5-InsP7.
Keywords:Nudix  Diphosphoinositol  Phosphohydrolase  CDK5RAP1
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