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    Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases


    Valizadeh, Mohsen and Schenk, Gerhard and Nash, Kevin and Oddie, Geoff W. and Guddat, Luke W. and Hume, David A. and de Jersey, John and Burke Jr., Terrence R. and Hamilton, Susan E. (2004) Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases. Archives of Biochemistry and Biophysics , 424. pp. 154-162. ISSN 0003-9861

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    Abstract

    Purple acid phosphatases are metal-containing hydrolases. While their precise biological role(s) is unknown, the mammalian enzyme has been linked in a variety of biological circumstances (e.g., osteoporosis) with increased bone resorption. Inhibition of the human enzyme is a possible strategy for the treatment of bone-resorptive diseases such as osteoporosis. Previously, we determined the crystal structure of pig purple acid phosphatase to 1.55A and we showed that it is a good model for the human enzyme. Here, a study of the pH dependence of its kinetic parameters showed that the pig enzyme is most efficient at pH values similar to those encountered in the osteoclast resorptive space. Based on the observation that phosphotyrosine-containing peptides are good substrates for pig purple acid phosphatase, peptides containing a range of phosphotyrosine mimetics were synthesized. Kinetic analysis showed that they act as potent inhibitors of mammalian and plant purple acid phosphatases, with the best inhibitors exhibiting low micromolar inhibition constants at pH 3–5. These compounds are thus the most potent organic inhibitors yet reported for the purple acid phosphatases.

    Item Type: Article
    Keywords: Purple acid phosphatase; Tartrate resistant acid phosphatase; Inhibition and kinetic studies; Phosphotyrosyl peptide; Osteoporosis;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 3720
    Depositing User: Gary Schenk
    Date Deposited: 31 May 2012 14:42
    Journal or Publication Title: Archives of Biochemistry and Biophysics
    Publisher: Elsevier
    Refereed: Yes
    URI:

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