Tartrate resistant acid phosphatase

Tartrate resistant acid phosphatase is a glycosylated monomeric metalloenzyme expressed in mammals.cite journal | author = Baumbach GA, Saunders PT, Ketcham CM, Bazer FW, Roberts RM | title = Uteroferrin contains complex and high mannose-type oligosaccharides when synthesized in vitro | journal = Mol. Cell. Biochem. | volume = 105 | issue = 2 | pages = 107–17 | year = 1991 | pmid = 1922010 | doi = | issn = ] It has a molecular weight of approximately 35kDa, a basic isoelectric point (7.6-9.5) , and optimal activity in acidic conditions. TRAP is synthesized as latent proenzyme and activated by proteolytic cleavage and reduction.cite journal | author = Ljusberg J, Ek-Rylander B, Andersson G | title = Tartrate-resistant purple acid phosphatase is synthesized as a latent proenzyme and activated by cysteine proteinases | journal = Biochem. J. | volume = 343 Pt 1 | issue = | pages = 63–9 | year = 1999 | pmid = 10493912 | doi = | issn = ] cite journal | author = Ljusberg J, Wang Y, Lång P, Norgård M, Dodds R, Hultenby K, Ek-Rylander B, Andersson G | title = Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts | journal = J. Biol. Chem. | volume = 280 | issue = 31 | pages = 28370–81 | year = 2005 | pmid = 15929988 | doi = 10.1074/jbc.M502469200 | issn = ] It is differentiated by other mammalian acid phosphatases by its resistance to inhibition by tartrate, molecular weights and characteristic purple colour.

The mechanism of phosphate ester hydrolysis by TRAP is through a nucleophilic attack mechanism,cite journal | author = Klabunde T, Sträter N, Fröhlich R, Witzel H, Krebs B | title = Mechanism of Fe(III)-Zn(II) purple acid phosphatase based on crystal structures | journal = J. Mol. Biol. | volume = 259 | issue = 4 | pages = 737–48 | year = 1996 | pmid = 8683579 | doi = 10.1006/jmbi.1996.0354 | issn = ] 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.cite journal | author = Burstone MS | title = Histochemical demonstration of acid phosphatase activity in osteoclasts | journal = J. Histochem. Cytochem. | volume = 7 | issue = 1 | pages = 39–41 | year = 1959 | pmid = 13664936 | doi = | issn = ] cite journal | author = Minkin C | title = Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function | journal = Calcif. Tissue Int. | volume = 34 | issue = 3 | pages = 285–90 | year = 1982 | pmid = 6809291 | doi = | issn = ] 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.

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.cite journal | author = Cassady AI, King AG, Cross NC, Hume DA | title = Isolation and characterization of the genes encoding mouse and human type-5 acid phosphatase | journal = Gene | volume = 130 | issue = 2 | pages = 201–7 | year = 1993 | pmid = 8359686 | doi = | issn = ] 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.cite journal | author = Walsh NC, Cahill M, Carninci P, Kawai J, Okazaki Y, Hayashizaki Y, Hume DA, Cassady AI | title = Multiple tissue-specific promoters control expression of the murine tartrate-resistant acid phosphatase gene | journal = Gene | volume = 307 | issue = | pages = 111–23 | year = 2003 | pmid = 12706893 | doi = 10.1016/S0378-1119(03)00449-9 | issn = ] 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.cite journal | author = Hayman AR, Jones SJ, Boyde A, Foster D, Colledge WH, Carlton MB, Evans MJ, Cox TM | title = Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis | journal = Development | volume = 122 | issue = 10 | pages = 3151–62 | year = 1996 | pmid = 8898228 | doi = | issn = | url = http://dev.biologists.org/cgi/content/abstract/122/10/3151 ] Likewise in TRAP overexpressing transgenic mice, mild osteoporosis occurred along with increased osteoblast activity and bone synthesis.cite journal | author = Angel NZ, Walsh N, Forwood MR, Ostrowski MC, Cassady AI, Hume DA | title = Transgenic mice overexpressing tartrate-resistant acid phosphatase exhibit an increased rate of bone turnover | journal = J. Bone Miner. Res. | volume = 15 | issue = 1 | pages = 103–10 | year = 2000 | pmid = 10646119 | doi = | issn = ] 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.cite journal | author = Ek-Rylander B, Flores M, Wendel M, Heinegård D, Andersson G | title = Dephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase. Modulation of osteoclast adhesion in vitro | journal = J. Biol. Chem. | volume = 269 | issue = 21 | pages = 14853–6 | year = 1994 | pmid = 8195113 | doi = | issn = ] 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).cite journal | author = Darden AG, Ries WL, Wolf WC, Rodriguiz RM, Key LL | title = Osteoclastic superoxide production and bone resorption: stimulation and inhibition by modulators of NADPH oxidase | journal = J. Bone Miner. Res. | volume = 11 | issue = 5 | pages = 671–5 | year = 1996 | pmid = 9157782 | doi = | issn = ] 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: [Fenton, H.J.H., Oxidation of tartaric acid in presence of iron. J Chem Soc Trans, 1894. 65: p. 899-910.]

: O₂ → (NADPH-oxidase) O^{2- ∙} → (superoxide dismutase) H₂O₂ → (catalase) H₂O + O₂: TRAP-Fe³⁺ (purple) + O^{2- ∙}→ TRAP-Fe²⁺ (pink) + O₂: H₂O₂ + TRAP-Fe²⁺ (pink) → HO^∙ + HO⁻ + 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.cite journal | author = Roberts RM, Raub TJ, Bazer FW | title = Role of uteroferrin in transplacental iron transport in the pig | journal = Fed. Proc. | volume = 45 | issue = 10 | pages = 2513–8 | year = 1986 | pmid = 3527760 | doi = | issn = ] 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.cite journal | author = Sheu TJ, Schwarz EM, Martinez DA, O'Keefe RJ, Rosier RN, Zuscik MJ, Puzas JE | title = A phage display technique identifies a novel regulator of cell differentiation | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 438–43 | year = 2003 | pmid = 12403789 | doi = 10.1074/jbc.M208292200 | issn = ]

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

External links

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