Tartrate-Resistant Acid Phosphatase: A Target for Anti-Osteoporotic Chemotherapeutics

Peter      Vella; Ross      P. McGeary; Lawrence      R. Gahan; Gerhard      Schenk

Abstract

Tartrate-resistant acid phosphatases (TRAcPs) belong to the family of binuclear metallohydrolases and catalyse the hydrolysis of a wide range of phosphomonoester and amide substrates. These enzymes have been characterised from numerous animal, plant and fungal sources. They are distinguished from other phosphatases by their resistance to inhibition by tartrate, their optimal catalytic efficiency at low pH and their characteristic purple colour, the latter due to an interaction between a conserved tyrosine residue in the active site and an Fe(III). Consequently, these enzymes are often referred to as purple acid phosphatases (PAPs). TRAcPs catalyse the hydrolysis of a range of substrates (including ATP) and are inhibited by the reaction product phosphate and related tetraoxo anions (i.e. molybdate, arsenate, vanadate), as well as fluoride. The interactions between these inhibitors and TRAcPs have been investigated with structural, kinetic and spectroscopic techniques, resulting in the proposal of a comprehensive eight-step reaction mechanism. In animals, TRAcP activity is directly linked to bone resorption; serum levels of the enzyme are therefore a main marker for the diagnosis of osteoporosis. Furthermore, high expression levels in macrophages during pathogen invasion indicate a pivotal role for TRAcPs in the immune response. TRAcP has thus emerged as a major target to develop chemotherapeutics to combat osteoporosis and other bone-related disorders. In this minireview, we will revisit recent developments in TRAcP inhibitor design and synthesis, and discuss how inhibitors have been pivotal in developing an increased understanding of the structure, function and mechanism of this enzyme.

Keywords: Tartrate-resistant acid phosphatase, purple acid phosphatase, osteoporosis, bone metabolism, reaction mechanism, drug design and development, Tartrate-resistant acid phosphatases (TRAcPs), metallohydrolases, phosphomonoester, purple acid phosphatases (PAPs), tetraoxo anions, spectroscopic techniques, homodimeric, reactive oxygen species (ROS), transgenic, proteolysis, proenzyme, dephosphorylation, endocytosis, osteoclasts, Staphylococcus aureus, phagocytosed, Arabidopsis thaliana, homo-divalent oxidation, chromophoric Fe(III), crystallographic, spectroscopic, electron-nuclear double resonance (ENDOR), sweet potato enzyme, mutagenesis, asparagine, bacteriophage λ, electron paramagnetic resonance (EPR), extended X-ray absorption fine structure, enzyme-phosphate complex, oxyanions, molybdate, phosphate, vanadate, tungstate, ethylphosphonic acid, naphthylenemethylphosphonic acids, bisbenzoyl