title: Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases.
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.
authors.affiliation: Department of Biochemistry, The University of Queensland, St. Lucia, Qld 4072, Australia.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Valizadeh
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schenk
authors.forename: Kevin
authors.initials: K
authors.lastname: Nash
authors.forename: Geoff W
authors.initials: GW
authors.lastname: Oddie
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: John
authors.initials: J
authors.lastname: de Jersey
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: Susan
authors.initials: S
authors.lastname: Hamilton
mesh_terms: D000135:Acid Phosphatase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D027723:Ipomoea batatas / Q000201:enzymology; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D027805:Phaseolus / Q000201:enzymology; D010748:Phosphopeptides / Q000737:chemistry*; D019000:Phosphotyrosine / Q000031:analogs & derivatives / Q000737:chemistry*; D011485:Protein Binding; D013045:Species Specificity; D013379:Substrate Specificity; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; D046911:Macromolecular Substances; D010748:Phosphopeptides; D019000:Phosphotyrosine; C091137:purple acid phosphatase; D000135:Acid Phosphatase