Structure, function, and regulation of tartrate-resistant acid phosphatase

Oddie, G.W.; Schenk, Gerhard; Angel, N.; Walsh, Nicole C.; Guddat, L.W.; Jersey, John de; Cassady, A. I.; Hamilton, Susan; Hume, David

doi:10.1016/s8756-3282(00)00368-9

Cited by 198 publications

(204 citation statements)

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“…The replacement of the Fe III by Mn II converts the acid phosphatase into a phosphatase that operates optimally under neutral pH conditions. It thus appears that PAP may have evolved from homodivalent ancestors in response to its biological function in often acidic environments (e.g., bone resorptive space and soil 8 ). Furthermore, the results presented in this study demonstrate the importance of having a trivalent metal ion for acid phosphatase activity, thus increasing our understanding of the role of the chromophoric metal ion as an activator of the nucleophile in acid hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent Mn^IIMn^II Active Site

et al. 2009

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Abstract:The currently accepted paradigm is that the purple acid phosphatases (PAPs) require a heterovalent, dinuclear metal-ion center for catalysis. It is believed that this is an essential feature for these enzymes in order for them to operate under acidic conditions. A PAP from sweet potato is unusual in that it appears to have a specific requirement for manganese, forming a unique Fe III -µ-(O)-Mn II center under catalytically optimal conditions (Schenk et al. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 273). Herein, we demonstrate, with detailed electron paramagnetic resonance (EPR) spectroscopic and kinetic studies, that in this enzyme the chromophoric Fe III can be replaced by Mn II , forming a catalytically active, unprecedented antiferromagnetically coupled homodivalent Mn II -µ-(H)OH-µ-carboxylato-Mn II center in a PAP. However, although the enzyme is still active, it no longer functions as an acid phosphatase, having optimal activity at neutral pH. Thus, PAPs may have evolved from distantly related divalent dinuclear metallohydrolases that operate under pH neutral conditions by stabilization of a trivalent-divalent metal-ion core. The present Mn II -Mn II system models these distant relatives, and the results herein make a significant contribution to our understanding of the role of the chromophoric metal ion as an activator of the nucleophile. In addition, the detailed analysis of strain broadened EPR spectra from exchange-coupled dinuclear Mn II -Mn II centers described herein provides the basis for the full interpretation of the EPR spectra from other dinuclear Mn metalloenzymes.

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Section: Discussionmentioning

confidence: 99%

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent Mn^IIMn^II Active Site

et al. 2009

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“…These include (i) the transport of iron from the mother to the developing foetus during gestation (14); (ii) bone resorption in osteoclasts (evidence for this activity is derived from the effect of PAP on osteoclasts that were cultured on cortical bone slices (15) and from the observation that the addition of anti-PAP antibodies to osteoclasts reduces in vitro resorption of bone (16)); (iii) an involvement in the inflammatory response of antigen presenting cells (17); and (iv) catalysis of Fenton's reaction, thus promoting the generation of reactive oxygen species (ROS). ROS can be targeted to destroy collagen and other proteins in resorbing osteoclasts.…”

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confidence: 99%

Identification of Purple Acid Phosphatase Inhibitors by Fragment‐Based Screening: Promising New Leads for Osteoporosis Therapeutics

et al. 2012

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Purple acid phosphatases are metalloenzymes found in animals, plants and fungi. They possess a binuclear metal centre to catalyse the hydrolysis of phosphate esters and anhydrides under acidic conditions. In humans, elevated purple acid phosphatases levels in sera are correlated with the progression of osteoporosis and metabolic bone malignancies, making this enzyme a target for the development of new chemotherapeutics to treat bone-related illnesses. To date, little progress has been achieved towards the design of specific and potent inhibitors of this enzyme that have drug-like properties. Here, we have undertaken a fragment-based screening approach using a 500-compound library identifying three inhibitors of purple acid phosphatases with K i values in the 30-60 lM range. Ligand efficiency values are 0.39-0.44 kcal ⁄ mol per heavy atom. X-ray crystal structures of these compounds in complex with a plant purple acid phosphatases (2.3-2.7 Å resolution) have been determined and show that all bind in the active site within contact of the binuclear centre. For one of these compounds, the phenyl ring is positioned within 3.5 Å of the binuclear centre. Docking simulations indicate that the three compounds fit into the active site of human purple acid phosphatases. These studies open the way to the design of more potent and selective inhibitors of purple acid phosphatases that can be tested as anti-osteoporotic drug leads.Key words: X-ray, crystallography, drug design, fragment screening, purple acid phosphatase, osteoporosis Purple acid phosphatases (PAP) are metalloenzymes that hydrolyse phosphate esters and anhydrides, generally at low pH values (1). The distinctive purple colour of these enzymes is due to a metal to ligand charge transfer from a tyrosine phenolate to a chromophoric Fe(III) (2,3). The cornerstone of the active site of PAP is the presence of two metal ions; Fe(III) is always present in the chromophoric site, while the second site can be occupied by a redox active Fe(II ⁄ III) in mammals (4,5) or a Zn(II) or Mn(II) in plants (6,7). Mammalian PAP is a 35 kDa monomeric protein also known as tartrate-resistant acid phosphatase (TRAP or TRAcP). In contrast, plant PAP is a 110 kDa homodimer, with each subunit consisting of two domains, an N-terminal one whose function is unknown and a catalytic C-terminal domain that strongly resembles the overall structure of the mammalian enzyme (1). Crystal structures of human (8), pig (9), rat (10,11) and plant PAPs (12,13) have been determined and show that the amino acid ligands of the metal ions are completely conserved across plant and animal PAPs, but there are some differences in the identities of the residues that line the active site.A number of biological roles for PAP have been proposed. These include (i) the transport of iron from the mother to the developing foetus during gestation (14); (ii) bone resorption in osteoclasts (evidence for this activity is derived from the effect of PAP on osteoclasts that were cultured on cortical bone slices (15) and from t...

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“…13,[21][22][23][24] Our interest in PAP as a potential therapeutic target lies in its association with osteoporosis. It is known that PAP is secreted into the bone-resorptive space in mammals, 2 and PAP activity has long been associated with bone resorption. 25 In addition, transgenic mice in which the PAP enzyme was over-expressed developed osteoporosis due to increased bone resorption, 26 whereas the corresponding knockout mice exhibited the opposite condition (osteopetrosis), further implicating the role of PAP in this process, 27 and establishing PAP as a drug target in the treatment of osteoporosis.…”

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confidence: 99%

Inhibition of purple acid phosphatase with α-alkoxynaphthylmethylphosphonic acids

McGeary

Vella

Mak

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tPurple acid phosphatases (PAPs) are binuclear hydrolases that catalyse the hydrolysis of a range of phosphorylated substrates. Human PAP is a major histochemical marker for the diagnosis of osteoporosis. In patients suffering from this disorder, PAP activity contributes to increased bone resorption and, therefore, human PAP is a key target for the development of anti-osteoporotic drugs. This manuscript describes the design and synthesis of derivatives of 1-naphthylmethylphosphonic acids as inhibitors of PAP. The K i values of these compounds are as low as 4 lM, the lowest reported to date for a PAP inhibitor.

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Structure, function, and regulation of tartrate-resistant acid phosphatase

Cited by 198 publications

References 120 publications

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent Mn^IIMn^II Active Site

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent Mn^IIMn^II Active Site

Identification of Purple Acid Phosphatase Inhibitors by Fragment‐Based Screening: Promising New Leads for Osteoporosis Therapeutics

Inhibition of purple acid phosphatase with α-alkoxynaphthylmethylphosphonic acids

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Structure, function, and regulation of tartrate-resistant acid phosphatase

Cited by 198 publications

References 120 publications

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent MnIIMnII Active Site

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent MnIIMnII Active Site

Identification of Purple Acid Phosphatase Inhibitors by Fragment‐Based Screening: Promising New Leads for Osteoporosis Therapeutics

Inhibition of purple acid phosphatase with α-alkoxynaphthylmethylphosphonic acids

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Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent Mn^IIMn^II Active Site

Metal-Ion Mutagenesis: Conversion of a Purple Acid Phosphatase from Sweet Potato to a Neutral Phosphatase with the Formation of an Unprecedented Catalytically Competent Mn^IIMn^II Active Site