Information about Tartrate Resistant Acid Phosphatase
acid phosphatase 5, tartrate resistant | |
| Identifiers | |
| Symbol | ACP5 |
| Entrez | 54 |
| HUGO | 124 |
| OMIM | 171640 |
| RefSeq | NM_001611 |
| UniProt | P13686 |
| Other data | |
| EC number | 3.1.3.2 |
| Locus | Chr. 19 p13.3-13.2 |
The mechanism of phosphate ester hydrolysis by TRAP is through a nucleophilic attack mechanism,[4] whereby, catalysis occurs with the binding of a phosphate-substrate to the Fe2+ in the active site of TRAP. This is then followed by a nucleophilic attack by a hydroxide ligand on the bound phosphorus atom resulting in cleavage of the phosphate ester bond and production of an alcohol. The exact identity and mechanism of the hydroxide ligand is unclear, but it is thought to be either a hydroxide that bridges the metal ions within the active site, or a terminal hydroxide bound to Fe3+, with conflicting reports for both mechanisms.
TRAP expression and cell localization
Normally, TRAP is highly expressed by osteoclast, activated macrophages, neurons and the porcine endometrium during pregnancy.[5][6] In newly born rats, lower levels are also detectable in the spleen, thymus, liver, kidneys, skin, lung and heart. There are also certain pathological conditions whereby expression of TRAP is increased. These include patients with leukaemic reticuloendotheliosis (hairy cell leukaemia), Gaucher’s disease, HIV-induced encephalopathy, osteoclastoma and in osteoporosis and metabolic bone diseases. In osteoclasts, TRAP is localized within the ruffled border area, lysosomes and in Golgi cisternae and vesicles.[3]TRAP gene, promoter organisation and transcription
Mammalian TRAP is encoded by one gene, which is localized on chromosome 19 (19p13.2-13.3) in humans, and on chromosome 9 in mice. TRAP DNA is, as expected from protein sequencing, highly conserved throughout the class mammalia. The TRAP gene has been cloned and sequenced in porcine, rat, human and murine species.[7] Human, murine and porcine TRAP genes all contain 5 exons and have the ATG codon at the beginning of exon 2, with exon 1 being non-coding. Within the exon 1 promoter there are three distinct “tissue-specific” promoters; 1A, 1B and 1C.[8] This would allow TRAP expression to be tightly controlled. Transcribed from this gene is a 1.5kb mRNA with an open reading frame (ORF) of 969-975 bp encoding a 323-325 amino acid protein. In the rat the ORF is 981bp in length and encodes for a 327 amino acid protein. TRAP is translated as a single polypeptide.Physiology
The exact physiological role(s) of TRAP is unknown, but many functions have been attributed to this protein. In knockout mice studies, those with a phenotype of TRAP-/- showed mild osteopetrosis, with greatly reduced osteoclast activity, resulting in thickening and shortening of the cortices, the formation of club-like deformities in the distal femur, and widened epiphyseal growth plates with delayed mineralization of cartilage, all of which increased with age.[9] Likewise in TRAP overexpressing transgenic mice, mild osteoporosis occurred along with increased osteoblast activity and bone synthesis.[10] Proposed functions of TRAP include osteopontin /bone sialoprotein dephosphorylation, the generation of reactive oxygen species (ROS), iron transport, and as a cell growth and differentiation factor.Protein dephosphorylation and osteoclast migration
It has been shown that osteopontin and bone sialoprotein, bone matrix phosphoproteins, are highly efficient in vitro TRAP substrates, which bind to osteoclasts when phosphorylated.[11] Upon partial dephosphorylation, both osteopontin and bone sialoprotein are incapable of binding to osteoclasts. From this effect, it has been hypothesized that TRAP is secreted from the ruffled border, dephosphorylates osteopontin and allows osteoclast migration, and further resorption to occur.ROS generation
Reactive oxygen species (ROS) are generated in macrophages and osteoclasts from superoxide (O2-.), which forms from the action of NADPH-oxidase on oxygen (O2).[12] They play an essential role in the function of phagocytic cells.TRAP, containing a redox active iron, catalyzes the generation of ROS through Fenton chemistry:[13]
- O2 → (NADPH-oxidase) O2- ∙ → (superoxide dismutase) H2O2 → (catalase) H2O + O2
- TRAP-Fe3+ (purple) + O2- ∙→ TRAP-Fe2+ (pink) + O2
- H2O2 + TRAP-Fe2+ (pink) → OH∙ + OH− + TRAP-Fe3+
producing hydroxyl radicals, hydrogen peroxide and singlet oxygen. In osteoclasts, ROS are generated at the ruffled border and seem to be required for resorption and degradation to occur.
Iron transport
In the pregnant sow, uteroferrin is highly expressed in the uterine fluids.[14] Due to the unique anatomy of the porcine uterus, and the specific, progesterone induced, expression of TRAP; it is hypothesized that uteroferrin acts as an iron transport protein.Cell growth and differentiation factor
TRAP is associated with osteoblast migration to bone resorption sites, and once there TRAP is believed to initiate osteoblast differentiation, activation and proliferation. This hypothesis was formed from the examination of the bone structure of TRAP-null mice. It was noted that, in addition to osteopetrosis, bone formation occurred in a haphazard manner, where the microarchitecture was highly irregular.[15]In TRAP overexpressing mice, it has been found that the affected mice are grossly obese. This has led to the hypothesis that TRAP has involvement in hyperplastic obesity.
References
1. ^ Baumbach, G.A., et al., Uteroferrin contains complex and high mannose-type oligosaccharides when synthesized in vitro. Mol Cell Biochem, 1991. 105(2): p. 107-17.
2. ^ Ljusberg, J., B. Ek-Rylander, and G. Andersson, Tartrate-resistant purple acid phosphatase is synthesized as a latent proenzyme and activated by cysteine proteinases. Biochem J, 1999. 343 Pt 1: p. 63-9.
3. ^ Ljusberg, J., et al., Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. J Biol Chem, 2005. 280(31): p. 28370-81.
4. ^ Klabunde, T., et al., Mechanism of Fe(III)-Zn(II) purple acid phosphatase based on crystal structures. J Mol Biol, 1996. 259(4): p. 737-48.
5. ^ Burstone, M.S., Histochemical demonstration of acid phosphatase activity in osteoclasts. J Histochem Cytochem, 1959. 7(1): p. 39-41.
6. ^ Minkin, C., Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif Tissue Int, 1982. 34(3): p. 285-90.
7. ^ Cassady, A.I., et al., Isolation and characterization of the genes encoding mouse and human type-5 acid phosphatase. Gene, 1993. 130(2): p. 201-7.
8. ^ Walsh, N.C., et al., Multiple tissue-specific promoters control expression of the murine tartrate-resistant acid phosphatase gene. Gene, 2003. 307: p. 111-23.
9. ^ Hayman, A.R., et al., Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development, 1996. 122(10): p. 3151-62.
10. ^ Angel, N.Z., et al., Transgenic mice overexpressing tartrate-resistant acid phosphatase exhibit an increased rate of bone turnover. J Bone Miner Res, 2000. 15(1): p. 103-10.
11. ^ Ek-Rylander, B., et al., Dephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase. Modulation of osteoclast adhesion in vitro. J Biol Chem, 1994. 269(21): p. 14853-6.
12. ^ Darden, A.G., et al., Osteoclastic superoxide production and bone resorption: stimulation and inhibition by modulators of NADPH oxidase. J Bone Miner Res, 1996. 11(5): p. 671-5.
13. ^ Fenton, H.J.H., Oxidation of tartaric acid in presence of iron. J Chem Soc Trans, 1894. 65: p. 899-910.
14. ^ Roberts, R.M., T.J. Raub, and F.W. Bazer, Role of uteroferrin in transplacental iron transport in the pig. Fed Proc, 1986. 45(10): p. 2513-8.
15. ^ Sheu, T.J., et al., A phage display technique identifies a novel regulator of cell differentiation. J Biol Chem, 2003. 278(1): p. 438-43.
2. ^ Ljusberg, J., B. Ek-Rylander, and G. Andersson, Tartrate-resistant purple acid phosphatase is synthesized as a latent proenzyme and activated by cysteine proteinases. Biochem J, 1999. 343 Pt 1: p. 63-9.
3. ^ Ljusberg, J., et al., Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. J Biol Chem, 2005. 280(31): p. 28370-81.
4. ^ Klabunde, T., et al., Mechanism of Fe(III)-Zn(II) purple acid phosphatase based on crystal structures. J Mol Biol, 1996. 259(4): p. 737-48.
5. ^ Burstone, M.S., Histochemical demonstration of acid phosphatase activity in osteoclasts. J Histochem Cytochem, 1959. 7(1): p. 39-41.
6. ^ Minkin, C., Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif Tissue Int, 1982. 34(3): p. 285-90.
7. ^ Cassady, A.I., et al., Isolation and characterization of the genes encoding mouse and human type-5 acid phosphatase. Gene, 1993. 130(2): p. 201-7.
8. ^ Walsh, N.C., et al., Multiple tissue-specific promoters control expression of the murine tartrate-resistant acid phosphatase gene. Gene, 2003. 307: p. 111-23.
9. ^ Hayman, A.R., et al., Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development, 1996. 122(10): p. 3151-62.
10. ^ Angel, N.Z., et al., Transgenic mice overexpressing tartrate-resistant acid phosphatase exhibit an increased rate of bone turnover. J Bone Miner Res, 2000. 15(1): p. 103-10.
11. ^ Ek-Rylander, B., et al., Dephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase. Modulation of osteoclast adhesion in vitro. J Biol Chem, 1994. 269(21): p. 14853-6.
12. ^ Darden, A.G., et al., Osteoclastic superoxide production and bone resorption: stimulation and inhibition by modulators of NADPH oxidase. J Bone Miner Res, 1996. 11(5): p. 671-5.
13. ^ Fenton, H.J.H., Oxidation of tartaric acid in presence of iron. J Chem Soc Trans, 1894. 65: p. 899-910.
14. ^ Roberts, R.M., T.J. Raub, and F.W. Bazer, Role of uteroferrin in transplacental iron transport in the pig. Fed Proc, 1986. 45(10): p. 2513-8.
15. ^ Sheu, T.J., et al., A phage display technique identifies a novel regulator of cell differentiation. J Biol Chem, 2003. 278(1): p. 438-43.
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An osteoclast (from the Greek words for "bone" and "broken") is a type of bone cell that removes bone tissue by removing the bone's mineralized matrix. This process is known as bone resorption.
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Macrophages (Greek: "big eaters", from makros "large" + phagein "eat") are cells within the tissues that originate from specific white blood cells called monocytes.
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Osteoporosis
Classification & external resources
ICD-10 M 80. -M 82.
ICD-9 733.0
DiseasesDB 9385
eMedicine med/1693 ped/1683
MeSH D010024 Osteoporosis is a disease of bone leading to an increased risk of fracture.
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Classification & external resources
ICD-10 M 80. -M 82.
ICD-9 733.0
DiseasesDB 9385
eMedicine med/1693 ped/1683
MeSH D010024 Osteoporosis is a disease of bone leading to an increased risk of fracture.
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protein sequencing - determining the amino acid sequences of its constituent peptides; and also determining what conformation it adopts and whether it is complexed with any non-peptide molecules.
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The femur or thigh bone is the longest, most voluminous, and strongest bone of mammalian bodies. It forms part of the hip and part of the knee.
The word femur is Latin for thigh.
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An osteoblast (from the Greek words for "bone" and "germ" or embryonic) is a mononucleate cell that is responsible for bone formation. Osteoblasts produce osteoid, which is composed mainly of Type I collagen.
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Osteopontin is a glycoprotein first identified in 1986 in osteoblasts. The prefix of the word "osteo" indicates that the protein is expressed in bone. Osteopontin is an extracellular structural protein and therefore an organic component of bone.
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Bone sialoprotein (BSP) is a component of mineralized tissues such as bone, dentin, cementum and calcified cartilage. BSP is a significant component of the bone extracellular matrix and has been suggested to constitute approximately 8% of all non-collagenous proteins found
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An osteoclast (from the Greek words for "bone" and "broken") is a type of bone cell that removes bone tissue by removing the bone's mineralized matrix. This process is known as bone resorption.
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Superoxide is the anion O2−. It is important as the product of the one-electron reduction of dioxygen, which occurs widely in nature.[1] With one unpaired electron, the superoxide ion is a free radical, and, like dioxygen, it is paramagnetic.
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