Tartrate-resistant acid phosphatase: Difference between revisions

'''Tartrate-resistant acid phosphatase''' ('''TRAP''' or '''TRAPase'''), also called '''acid phosphatase 5, tartrate resistant''' ('''ACP5'''), is a [[glycosylated]] [[monomer]]ic [[metalloprotein]] [[enzyme]] expressed in mammals.<ref name="pmid1922010">{{cite journal | vauthors = 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.Molecular Cell.and Biochem.Cellular Biochemistry | volume = 105 | issue = 2 | pages = 107–17107–117 | yeardate = July 1991 | pmid = 1922010 | doi = 10.1007/bf00227750 | s2cid = 30416983 }}</ref> 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.<ref name="pmid10493912">{{cite journal | vauthors = 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.The J.Biochemical Journal | volume = 343 Pt 1 | issue = 1 | pages = 63–963–69 | yeardate = October 1999 | pmid = 10493912 | pmc = 1220524 | doi = 10.1042/0264-6021:3430063 }}</ref><ref name="Ljusberg2005">{{cite journal | vauthors = Ljusberg J, Wang Y, Lång P, Norgård M, Dodds R, Hultenby K, Ek-Rylander B, Andersson G | display-authors = 6 | title = Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 280 | issue = 31 | pages = 28370–8128370–28381 | yeardate = August 2005 | pmid = 15929988 | doi = 10.1074/jbc.M502469200 | doi-access = free }}</ref> It is differentiated from other mammalian acid [[phosphatase]]s by its resistance to inhibition by [[tartrate]] and by its molecular weight.

The mechanism of phosphate ester hydrolysis by TRAP is through a nucleophilic attack mechanism,<ref name="pmid8683579">{{cite journal | vauthors = 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.Journal Mol.of Molecular Biol.Biology | volume = 259 | issue = 4 | pages = 737–48737–748 | yeardate = June 1996 | pmid = 8683579 | doi = 10.1006/jmbi.1996.0354 }}</ref> 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.

Under normal circumstances, TRAP is highly expressed by [[osteoclast]]s, activated [[macrophages]], [[neurons]], and by the porcine endometrium during pregnancy.<ref name="pmid13664936">{{cite journal | authorvauthors = Burstone MS | title = Histochemical demonstration of acid phosphatase activity in osteoclasts | journal = J.The Histochem.Journal Cytochem.of Histochemistry and Cytochemistry | volume = 7 | issue = 1 | pages = 39–41 | yeardate = January 1959 | pmid = 13664936 | doi = 10.1177/7.1.39 | doi-access = free }}</ref><ref name="pmid6809291">{{cite journal | authorvauthors = Minkin C | title = Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function | journal = Calcif.Calcified Tissue Int.International | volume = 34 | issue = 3 | pages = 285–90285–290 | yeardate = May 1982 | pmid = 6809291 | doi = 10.1007/BF02411252 | s2cid = 22706943 }}</ref> In newborn rats, TRAP is also detectable in the spleen, thymus, liver, kidneys, skin, lung, and heart at low levels. TRAP expression is increased in certain pathological conditions. These include leukaemic reticuloendotheliosis ([[hairy cell leukaemia]]), [[Gaucher’sGaucher's disease]], [[HIV-induced encephalopathy]], [[osteoclastoma]] and [[osteoporosis]], and metabolic bone diseases.

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.<ref name="pmid8359686">{{cite journal | vauthors = 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 = 201–7201–207 | yeardate = August 1993 | pmid = 8359686 | doi = 10.1016/0378-1119(93)90420-8 }}</ref>

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” [[promotor (biology)|promoters]]: 1A, 1B, and 1C.<ref name="pmid12706893">{{cite journal | vauthors = Walsh NC, Cahill M, Carninci P, Kawai J, Okazaki Y, Hayashizaki Y, Hume DA, Cassady AI | display-authors = 6 | title = Multiple tissue-specific promoters control expression of the murine tartrate-resistant acid phosphatase gene | journal = Gene | volume = 307 | pages = 111–23111–123 | yeardate = March 2003 | pmid = 12706893 | doi = 10.1016/S0378-1119(03)00449-9 }}</ref> 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 981 bp in length and encodes for a 327-amino acid protein. TRAP is translated as a single polypeptide.

TRAP gene transcription is regulated by the [[Microphthalmia-associated transcription factor]].<ref name="pmid10750559">{{cite journal | vauthors = Luchin A, Purdom G, Murphy K, Clark MY, Angel N, Cassady AI, Hume DA, Ostrowski MC | display-authors = 6 | title = The microphthalmia transcription factor reulatesregulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts | journal = J.Journal of Bone Miner.and Res.Mineral Research | volume = 15 | issue = 3 | pages = 451–460 | yeardate = March 2000 | pmid = 10750559 | doi = 10.1359/jbmr.2000.15.3.451 | s2cid = 24064612 | doi-access = free }}</ref><ref name="pmidunknown">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | display-authors = 6 | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Res.Research | volume = 21 | issue = 6 | pages = 665–76665–676 | yeardate = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x | s2cid = 24698373 | doi-access = free }}</ref>

==Physiology and pathology==

In knockout studies, TRAP^−/− mice exhibit mild [[osteopetrosis]], associated with reduced osteoclast activity. These result in thickening and shortening of the cortices, formation of club-like deformities in the distal [[femur]], and widened epiphyseal growth plates with delayed mineralization of cartilage, all of which increase with age.<ref name="pmid8898228">{{cite journal | vauthors = Hayman AR, Jones SJ, Boyde A, Foster D, Colledge WH, Carlton MB, Evans MJ, Cox TM | display-authors = 6 | title = Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis | journal = Development | volume = 122 | issue = 10 | pages = 3151–623151–3162 | yeardate = October 1996 | doi = 10.1242/dev.122.10.3151 | pmid = 8898228 | url = http://dev.biologists.org/cgi/content/abstract/122/10/3151 }}</ref> In TRAP overexpressing transgenic mice, mild osteoporosis occurs along with increased [[osteoblast]] activity and [[bone synthesis]].<ref name="pmid10646119">{{cite journal | vauthors = 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.Journal of Bone Miner.and Res.Mineral Research | volume = 15 | issue = 1 | pages = 103–10103–110 | yeardate = January 2000 | pmid = 10646119 | doi = 10.1359/jbmr.2000.15.1.103 | s2cid = 35584934 }}</ref>

It has been shown that osteopontin and bone sialoprotein, bone matrix phosphoproteins, are highly efficient ''in vitro'' TRAP [[Substrate (biochemistry)|substrates]], which bind to osteoclasts when phosphorylated.<ref name="pmid8195113">{{cite journal | vauthors = 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.The Biol.Journal Chem.of Biological Chemistry | volume = 269 | issue = 21 | pages = 14853–614853–14856 | yeardate = May 1994 | doi = 10.1016/S0021-9258(17)36541-9 | pmid = 8195113 | doi-access = free }}</ref> 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.

Reactive oxygen species (ROS) are generated in macrophages and osteoclasts from [[superoxide]] (O₂^−.), which forms from the action of NADPH-oxidase on oxygen (O₂).<ref name="pmid9157782">{{cite journal | vauthors = 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.Journal of Bone Miner.and Res.Mineral Research | volume = 11 | issue = 5 | pages = 671–5671–675 | yeardate = May 1996 | pmid = 9157782 | doi = 10.1002/jbmr.5650110515 | s2cid = 32443917 }}</ref> 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:<ref>{{cite journal | vauthors = Fenton, H.J.H.,HJ Oxidation| title = LXXIII.—Oxidation of tartaric acid in presence of iron. J| Chemjournal Soc= TransJournal of the Chemical Society, Transactions | date = 1894. | volume = 65: p| pages = 899–910 | doi = 10.1039/CT8946500899 899-910| url = https://zenodo.org/record/1429692 }}</ref>

In the pregnant sow, uteroferrin is highly expressed in the uterine fluids.<ref name="pmid3527760">{{cite journal | vauthors = Roberts RM, Raub TJ, Bazer FW | title = Role of uteroferrin in transplacental iron transport in the pig | journal = Fed.Federation Proc.Proceedings | volume = 45 | issue = 10 | pages = 2513–82513–2518 | yeardate = September 1986 | pmid = 3527760 }}</ref> 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.

TRAP is associated with osteoclast [[cell migration|migration]] to bone resorption sites, and, once there, TRAP is believed to initiate osteoclast differentiation, activation, and [[cell proliferation|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.<ref name="pmid12403789">{{cite journal | vauthors = 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.The Biol.Journal Chem.of Biological Chemistry | volume = 278 | issue = 1 | pages = 438–43438–443 | yeardate = January 2003 | pmid = 12403789 | doi = 10.1074/jbc.M208292200 | doi-access = free }}</ref>

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