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Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases
Authors:Valizadeh Mohsen  Schenk Gerhard  Nash Kevin  Oddie Geoff W  Guddat Luke W  Hume David A  de Jersey John  Burke Terrence R  Hamilton Susan
Affiliation:Department of Biochemistry, The University of Queensland, St. Lucia, Qld 4072, Australia.
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.
Keywords:Purple acid phosphatase   Tartrate resistant acid phosphatase   Inhibition and kinetic studies   Phosphotyrosyl peptide   Osteoporosis
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