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.
Phosphotyrosyl peptides and analogues as substrates
and inhibitors of purple acid phosphatases.
Archives of Biochemistry and Biophysics , 424.
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.
||Purple acid phosphatase; Tartrate resistant acid phosphatase; Inhibition and kinetic studies; Phosphotyrosyl peptide; Osteoporosis;
||Faculty of Science and Engineering > Chemistry
||31 May 2012 14:42
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