PPBT_MOUSE
ID PPBT_MOUSE Reviewed; 524 AA.
AC P09242; Q6P1B0;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Alkaline phosphatase, tissue-nonspecific isozyme {ECO:0000303|PubMed:10620060, ECO:0000303|PubMed:7789278};
DE Short=AP-TNAP;
DE Short=TNAP {ECO:0000303|PubMed:7789278};
DE Short=TNSALP {ECO:0000303|PubMed:10620060};
DE EC=3.1.3.1 {ECO:0000269|PubMed:23942722};
DE AltName: Full=Alkaline phosphatase 2;
DE AltName: Full=Alkaline phosphatase liver/bone/kidney isozyme;
DE AltName: Full=Phosphoamidase {ECO:0000305};
DE AltName: Full=Phosphocreatine phosphatase {ECO:0000303|PubMed:33981039};
DE EC=3.9.1.1 {ECO:0000269|PubMed:33981039};
DE Flags: Precursor;
GN Name=Alpl {ECO:0000303|PubMed:32035618, ECO:0000312|MGI:MGI:87983};
GN Synonyms=Akp-2, Akp2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=3478679; DOI=10.1073/pnas.84.20.7051;
RA Terao M., Mintz B.;
RT "Cloning and characterization of a cDNA coding for mouse placental alkaline
RT phosphatase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:7051-7055(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Forelimb;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-6.
RX PubMed=2165496; DOI=10.1016/s0021-9258(19)38283-3;
RA Brown N.A., Stofko R.E., Uhler M.D.;
RT "Induction of alkaline phosphatase in mouse L cells by overexpression of
RT the catalytic subunit of cAMP-dependent protein kinase.";
RL J. Biol. Chem. 265:13181-13189(1990).
RN [6]
RP DEVELOPMENTAL STAGE.
RX PubMed=7789278; DOI=10.1242/dev.121.5.1487;
RA MacGregor G.R., Zambrowicz B.P., Soriano P.;
RT "Tissue non-specific alkaline phosphatase is expressed in both embryonic
RT and extraembryonic lineages during mouse embryogenesis but is not required
RT for migration of primordial germ cells.";
RL Development 121:1487-1496(1995).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=7550313; DOI=10.1038/ng0995-45;
RA Waymire K.G., Mahuren J.D., Jaje J.M., Guilarte T.R., Coburn S.P.,
RA MacGregor G.R.;
RT "Mice lacking tissue non-specific alkaline phosphatase die from seizures
RT due to defective metabolism of vitamin B-6.";
RL Nat. Genet. 11:45-51(1995).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9056646;
RX DOI=10.1002/(sici)1097-0177(199703)208:3<432::aid-aja13>3.0.co;2-1;
RA Narisawa S., Froehlander N., Millan J.L.;
RT "Inactivation of two mouse alkaline phosphatase genes and establishment of
RT a model of infantile hypophosphatasia.";
RL Dev. Dyn. 208:432-446(1997).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=10620060; DOI=10.1359/jbmr.1999.14.12.2015;
RA Fedde K.N., Blair L., Silverstein J., Coburn S.P., Ryan L.M.,
RA Weinstein R.S., Waymire K., Narisawa S., Millan J.L., MacGregor G.R.,
RA Whyte M.P.;
RT "Alkaline phosphatase knock-out mice recapitulate the metabolic and
RT skeletal defects of infantile hypophosphatasia.";
RL J. Bone Miner. Res. 14:2015-2026(1999).
RN [10]
RP FUNCTION.
RX PubMed=11004006; DOI=10.1152/ajpregu.2000.279.4.r1365;
RA Johnson K.A., Hessle L., Vaingankar S., Wennberg C., Mauro S., Narisawa S.,
RA Goding J.W., Sano K., Millan J.L., Terkeltaub R.;
RT "Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and
RT regulates PC-1.";
RL Am. J. Physiol. 279:R1365-R1377(2000).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=11028439; DOI=10.1359/jbmr.2000.15.10.1879;
RA Wennberg C., Hessle L., Lundberg P., Mauro S., Narisawa S., Lerner U.H.,
RA Millan J.L.;
RT "Functional characterization of osteoblasts and osteoclasts from alkaline
RT phosphatase knockout mice.";
RL J. Bone Miner. Res. 15:1879-1888(2000).
RN [12]
RP DISRUPTION PHENOTYPE.
RX PubMed=11169525;
RX DOI=10.1002/1096-9896(2000)9999:9999<::aid-path722>3.0.co;2-y;
RA Narisawa S., Wennberg C., Millan J.L.;
RT "Abnormal vitamin B6 metabolism in alkaline phosphatase knock-out mice
RT causes multiple abnormalities, but not the impaired bone mineralization.";
RL J. Pathol. 193:125-133(2001).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=12082181; DOI=10.1073/pnas.142063399;
RA Hessle L., Johnson K.A., Anderson H.C., Narisawa S., Sali A., Goding J.W.,
RA Terkeltaub R., Millan J.L.;
RT "Tissue-nonspecific alkaline phosphatase and plasma cell membrane
RT glycoprotein-1 are central antagonistic regulators of bone
RT mineralization.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:9445-9449(2002).
RN [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=14982838; DOI=10.1016/s0002-9440(10)63172-0;
RA Anderson H.C., Sipe J.B., Hessle L., Dhanyamraju R., Atti E., Camacho N.P.,
RA Millan J.L., Dhamyamraju R.;
RT "Impaired calcification around matrix vesicles of growth plate and bone in
RT alkaline phosphatase-deficient mice.";
RL Am. J. Pathol. 164:841-847(2004).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-140; ASN-230; ASN-303 AND
RP ASN-430.
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-110, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Lung, Pancreas, Spleen, and
RC Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=19874193; DOI=10.1359/jbmr.091023;
RA Ciancaglini P., Yadav M.C., Simao A.M., Narisawa S., Pizauro J.M.,
RA Farquharson C., Hoylaerts M.F., Millan J.L.;
RT "Kinetic analysis of substrate utilization by native and TNAP-, NPP1-, or
RT PHOSPHO1-deficient matrix vesicles.";
RL J. Bone Miner. Res. 25:716-723(2010).
RN [18]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20684022; DOI=10.1002/jbmr.195;
RA Yadav M.C., Simao A.M., Narisawa S., Huesa C., McKee M.D., Farquharson C.,
RA Millan J.L.;
RT "Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1
RT and alkaline phosphatase function: a unified model of the mechanisms of
RT initiation of skeletal calcification.";
RL J. Bone Miner. Res. 26:286-297(2011).
RN [19]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=23942722; DOI=10.1007/s00223-013-9745-3;
RA Simao A.M., Bolean M., Hoylaerts M.F., Millan J.L., Ciancaglini P.;
RT "Effects of pH on the production of phosphate and pyrophosphate by matrix
RT vesicles' biomimetics.";
RL Calcif. Tissue Int. 93:222-232(2013).
RN [20]
RP FUNCTION.
RX PubMed=23427088; DOI=10.1002/jbmr.1901;
RA Narisawa S., Yadav M.C., Millan J.L.;
RT "In vivo overexpression of tissue-nonspecific alkaline phosphatase
RT increases skeletal mineralization and affects the phosphorylation status of
RT osteopontin.";
RL J. Bone Miner. Res. 28:1587-1598(2013).
RN [21]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=23825434; DOI=10.1523/jneurosci.0133-13.2013;
RA Street S.E., Kramer N.J., Walsh P.L., Taylor-Blake B., Yadav M.C.,
RA King I.F., Vihko P., Wightman R.M., Millan J.L., Zylka M.J.;
RT "Tissue-nonspecific alkaline phosphatase acts redundantly with PAP and NT5E
RT to generate adenosine in the dorsal spinal cord.";
RL J. Neurosci. 33:11314-11322(2013).
RN [22]
RP FUNCTION.
RX PubMed=26457330; DOI=10.1016/j.bbrep.2015.09.013;
RA Huesa C., Houston D., Kiffer-Moreira T., Yadav M.M., Millan J.L.,
RA Farquharson C.;
RT "The functional co-operativity of Tissue-nonspecific alkaline phosphatase
RT (TNAP) and PHOSPHO1 during initiation of skeletal mineralization.";
RL Biochem. Biophys. Rep. 4:196-201(2015).
RN [23]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=29174347; DOI=10.1016/j.bmcl.2017.11.024;
RA Pinkerton A.B., Sergienko E., Bravo Y., Dahl R., Ma C.T., Sun Q.,
RA Jackson M.R., Cosford N.D.P., Millan J.L.;
RT "Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-
RT 425), a potent and orally bioavailable tissue-nonspecific alkaline
RT phosphatase (TNAP) inhibitor.";
RL Bioorg. Med. Chem. Lett. 28:31-34(2018).
RN [24]
RP FUNCTION.
RX PubMed=32035618; DOI=10.1016/j.bbrc.2020.01.136;
RA Nakamura T., Nakamura-Takahashi A., Kasahara M., Yamaguchi A., Azuma T.;
RT "Tissue-nonspecific alkaline phosphatase promotes the osteogenic
RT differentiation of osteoprogenitor cells.";
RL Biochem. Biophys. Res. Commun. 524:702-709(2020).
RN [25]
RP FUNCTION.
RX PubMed=32028019; DOI=10.1016/j.bone.2020.115262;
RA Bessueille L., Briolay A., Como J., Mebarek S., Mansouri C., Gleizes M.,
RA El Jamal A., Buchet R., Dumontet C., Matera E.L., Mornet E., Millan J.L.,
RA Fonta C., Magne D.;
RT "Tissue-nonspecific alkaline phosphatase is an anti-inflammatory
RT nucleotidase.";
RL Bone 133:115262-115262(2020).
RN [26]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP INDUCTION BY COLD, AND DISRUPTION PHENOTYPE.
RX PubMed=33981039; DOI=10.1038/s41586-021-03533-z;
RA Sun Y., Rahbani J.F., Jedrychowski M.P., Riley C.L., Vidoni S.,
RA Bogoslavski D., Hu B., Dumesic P.A., Zeng X., Wang A.B., Knudsen N.H.,
RA Kim C.R., Marasciullo A., Millan J.L., Chouchani E.T., Kazak L.,
RA Spiegelman B.M.;
RT "Mitochondrial TNAP controls thermogenesis by hydrolysis of
RT phosphocreatine.";
RL Nature 593:580-585(2021).
CC -!- FUNCTION: Alkaline phosphatase that metabolizes various phosphate
CC compounds and plays a key role in skeletal mineralization and adaptive
CC thermogenesis (PubMed:10620060, PubMed:11028439, PubMed:14982838,
CC PubMed:23942722, PubMed:33981039). Has broad substrate specificity and
CC can hydrolyze a considerable variety of compounds: however, only a few
CC substrates, such as diphosphate (inorganic pyrophosphate; PPi),
CC pyridoxal 5'-phosphate (PLP) and N-phosphocreatine are natural
CC substrates (PubMed:19874193, PubMed:23942722, PubMed:33981039). Plays
CC an essential role in skeletal and dental mineralization via its ability
CC to hydrolyze extracellular diphosphate, a potent mineralization
CC inhibitor, to phosphate: it thereby promotes hydroxyapatite crystal
CC formation and increases inorganic phosphate concentration
CC (PubMed:9056646, PubMed:10620060, PubMed:11004006, PubMed:11028439,
CC PubMed:12082181, PubMed:14982838, PubMed:32035618). Acts in a non-
CC redundant manner with PHOSPHO1 in skeletal mineralization: while
CC PHOSPHO1 mediates the initiation of hydroxyapatite crystallization in
CC the matrix vesicles (MVs), ALPL/TNAP catalyzes the spread of
CC hydroxyapatite crystallization in the extracellular matrix
CC (PubMed:20684022, PubMed:26457330). Also promotes dephosphorylation of
CC osteopontin (SSP1), an inhibitor of hydroxyapatite crystallization in
CC its phosphorylated state; it is however unclear whether ALPL/TNAP
CC mediates SSP1 dephosphorylation via a direct or indirect manner
CC (PubMed:23427088). Catalyzes dephosphorylation of PLP to pyridoxal
CC (PL), the transportable form of vitamin B6, in order to provide a
CC sufficient amount of PLP in the brain, an essential cofactor for
CC enzymes catalyzing the synthesis of diverse neurotransmitters
CC (PubMed:7550313). Additionally, also able to mediate ATP degradation in
CC a stepwise manner to adenosine, thereby regulating the availability of
CC ligands for purinergic receptors (PubMed:19874193, PubMed:23942722,
CC PubMed:23825434, PubMed:32028019). Also capable of dephosphorylating
CC microbial products, such as lipopolysaccharides (LPS) as well as other
CC phosphorylated small-molecules, such as poly-inosine:cytosine (poly
CC I:C) (By similarity). Acts as a key regulator of adaptive thermogenesis
CC as part of the futile creatine cycle: localizes to the mitochondria of
CC thermogenic fat cells and acts by mediating hydrolysis of N-
CC phosphocreatine to initiate a futile cycle of creatine
CC dephosphorylation and phosphorylation (PubMed:33981039). During the
CC futile creatine cycle, creatine and N-phosphocreatine are in a futile
CC cycle, which dissipates the high energy charge of N-phosphocreatine as
CC heat without performing any mechanical or chemical work
CC (PubMed:33981039). {ECO:0000250|UniProtKB:P05186,
CC ECO:0000269|PubMed:10620060, ECO:0000269|PubMed:11004006,
CC ECO:0000269|PubMed:11028439, ECO:0000269|PubMed:12082181,
CC ECO:0000269|PubMed:14982838, ECO:0000269|PubMed:19874193,
CC ECO:0000269|PubMed:20684022, ECO:0000269|PubMed:23427088,
CC ECO:0000269|PubMed:23825434, ECO:0000269|PubMed:23942722,
CC ECO:0000269|PubMed:26457330, ECO:0000269|PubMed:32028019,
CC ECO:0000269|PubMed:32035618, ECO:0000269|PubMed:33981039,
CC ECO:0000269|PubMed:7550313, ECO:0000269|PubMed:9056646}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a phosphate monoester + H2O = an alcohol + phosphate;
CC Xref=Rhea:RHEA:15017, ChEBI:CHEBI:15377, ChEBI:CHEBI:30879,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:67140; EC=3.1.3.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10042,
CC ECO:0000269|PubMed:19874193, ECO:0000269|PubMed:23942722};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15018;
CC Evidence={ECO:0000269|PubMed:19874193, ECO:0000269|PubMed:23942722,
CC ECO:0000269|PubMed:29174347};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=diphosphate + H2O = H(+) + 2 phosphate; Xref=Rhea:RHEA:24576,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:43474; Evidence={ECO:0000269|PubMed:19874193,
CC ECO:0000269|PubMed:23942722, ECO:0000269|PubMed:29174347};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24577;
CC Evidence={ECO:0000269|PubMed:19874193, ECO:0000269|PubMed:23942722,
CC ECO:0000269|PubMed:29174347};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + pyridoxal 5'-phosphate = phosphate + pyridoxal;
CC Xref=Rhea:RHEA:20533, ChEBI:CHEBI:15377, ChEBI:CHEBI:17310,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:597326;
CC Evidence={ECO:0000250|UniProtKB:P05186};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20534;
CC Evidence={ECO:0000250|UniProtKB:P05186};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + phosphoethanolamine = ethanolamine + phosphate;
CC Xref=Rhea:RHEA:16089, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57603, ChEBI:CHEBI:58190;
CC Evidence={ECO:0000250|UniProtKB:P05186};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16090;
CC Evidence={ECO:0000250|UniProtKB:P05186};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-phosphocreatine = creatine + phosphate;
CC Xref=Rhea:RHEA:12977, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57947, ChEBI:CHEBI:58092; EC=3.9.1.1;
CC Evidence={ECO:0000269|PubMed:33981039};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12978;
CC Evidence={ECO:0000269|PubMed:33981039};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:19874193};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13066;
CC Evidence={ECO:0000269|PubMed:19874193};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ADP + H2O = AMP + H(+) + phosphate; Xref=Rhea:RHEA:61436,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:456215, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:19874193};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61437;
CC Evidence={ECO:0000269|PubMed:19874193};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=AMP + H2O = adenosine + phosphate; Xref=Rhea:RHEA:29375,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:16335, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:456215; Evidence={ECO:0000269|PubMed:23825434,
CC ECO:0000269|PubMed:23942722};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:29376;
CC Evidence={ECO:0000269|PubMed:23825434, ECO:0000269|PubMed:23942722};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P05187};
CC Note=Binds 1 Mg(2+) ion. {ECO:0000250|UniProtKB:P05187};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P05187};
CC Note=Binds 2 Zn(2+) ions. {ECO:0000250|UniProtKB:P05187};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:P05186};
CC -!- ACTIVITY REGULATION: Phosphatase activity is specifically inhibited by
CC 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425).
CC {ECO:0000269|PubMed:29174347, ECO:0000269|PubMed:33981039}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P05186}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P05186};
CC Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P05186}. Extracellular
CC vesicle membrane {ECO:0000269|PubMed:19874193,
CC ECO:0000269|PubMed:23942722}; Lipid-anchor, GPI-anchor
CC {ECO:0000269|PubMed:33981039}. Mitochondrion membrane
CC {ECO:0000269|PubMed:33981039}; Lipid-anchor, GPI-anchor
CC {ECO:0000269|PubMed:33981039}. Mitochondrion intermembrane space
CC {ECO:0000269|PubMed:33981039}. Note=Localizes to special class of
CC extracellular vesicles, named matrix vesicles (MVs), which are released
CC by osteogenic cells (PubMed:19874193, PubMed:23942722). Localizes to
CC the mitochondria of thermogenic fat cells: tethered to mitochondrial
CC membranes via a GPI-anchor and probably resides in the mitochondrion
CC intermembrane space (PubMed:33981039). {ECO:0000269|PubMed:19874193,
CC ECO:0000269|PubMed:23942722, ECO:0000269|PubMed:33981039}.
CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:3478679). Expressed in DRG
CC neurons and spinal cord neurons (PubMed:23825434).
CC {ECO:0000269|PubMed:23825434, ECO:0000269|PubMed:3478679}.
CC -!- DEVELOPMENTAL STAGE: Not expressed prior to gastrulation in embryo,
CC while it is expressed before in extraembryonic lineage cells destined
CC to form the chorion (PubMed:7789278). Expressed in both embryonic and
CC extraembryonic lineages during mouse embryogenesis (PubMed:7789278).
CC {ECO:0000269|PubMed:7789278}.
CC -!- INDUCTION: By cold: up-regulated in response to cold both in brown and
CC beige fat cells. {ECO:0000269|PubMed:33981039}.
CC -!- DOMAIN: Calcium-binding is structural and does not influence the
CC alkaline phosphatase activity. At very high concentrations, calcium can
CC however substitute for zinc at zinc-binding sites, leading to strongly
CC reduced enzyme activity. {ECO:0000250|UniProtKB:P05186}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:P05186}.
CC -!- DISRUPTION PHENOTYPE: Early death caused by defective metabolism of
CC vitamin B6 (PubMed:7550313). At about two weeks of age, mice display
CC seizures from which they die (PubMed:7550313, PubMed:9056646). Seizures
CC are caused by a defect in the metabolism of pyridoxal 5'-phosphate
CC (PLP) similar to that found in patients with hypophosphatasia, which
CC ultimately results in a decrease in levels of 4-aminobutanoate (GABA)
CC in the brain (PubMed:7550313). Mice do not show defects in skeletal
CC formation during the first 8 days of life (PubMed:7550313,
CC PubMed:10620060). Skeletal defects first appear at approximately 10
CC days of age and are characterized by worsening rachitic changes,
CC osteopenia and fracture (PubMed:9056646, PubMed:10620060). Osteoblasts
CC differentiate normally but are unable to initiate mineralization:
CC histologic studies reveal developmental arrest of chondrocyte
CC differentiation in epiphyses and in growth plates with diminished or
CC absent hypertrophic zones (PubMed:10620060, PubMed:11028439). Mineral
CC crystals are initiated within matrix vesicles (MVs) of the growth plate
CC and bone; however, mineral crystal proliferation and growth is
CC inhibited in the matrix surrounding MVs, as in the case with
CC hypophosphatasia (PubMed:14982838). Progressive osteoidosis from
CC defective skeletal matrix mineralization is observed but not associated
CC with features of secondary hyperparathyroidism (PubMed:10620060).
CC Abnormal vitamin B6 metabolism is not the cause of impaired bone
CC mineralization (PubMed:11169525). An accumulation of substrates is
CC observed, characterized by strong elevation of urinary diphosphate
CC (PPi) and phosphoethanolamine (PEA) levels and a striking accumulation
CC of plasma PLP (PubMed:10620060). Mice lacking both Phospho1 and Alpl
CC show a complete absence of skeletal mineralization, leading to
CC perinatal lethality (PubMed:20684022). Bone mineralization in mice
CC lacking both Enpp1 and Alpl is essentially normal, demonstrating that
CC Enpp1 and Alpl are antagonist key regulators of bone mineralization by
CC determining the normal steady-state levels of diphosphate (PPi)
CC (PubMed:12082181). Conditional deletion in adipocytes leads to
CC defective adaptive thermogenesis: defects are caused by abolition of
CC the futile creatine cycle, thereby reducing whole-body energy
CC expenditure and leading to rapid-onset obesity in mice, with no change
CC in movement or feeding behavior (PubMed:33981039).
CC {ECO:0000269|PubMed:10620060, ECO:0000269|PubMed:11028439,
CC ECO:0000269|PubMed:11169525, ECO:0000269|PubMed:12082181,
CC ECO:0000269|PubMed:14982838, ECO:0000269|PubMed:20684022,
CC ECO:0000269|PubMed:33981039, ECO:0000269|PubMed:7550313,
CC ECO:0000269|PubMed:9056646}.
CC -!- MISCELLANEOUS: In most mammals there are four different isozymes:
CC placental (ALPP), germ cell (ALPG), intestinal (ALPI) and tissue non-
CC specific (liver/bone/kidney) (ALPL/TNAP). {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the alkaline phosphatase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; J02980; AAA39928.1; -; mRNA.
DR EMBL; AK161780; BAE36569.1; -; mRNA.
DR EMBL; AK167023; BAE39196.1; -; mRNA.
DR EMBL; AL805954; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL807764; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC065175; AAH65175.1; -; mRNA.
DR EMBL; M54798; AAA37217.1; -; mRNA.
DR CCDS; CCDS18821.1; -.
DR RefSeq; NP_001274101.1; NM_001287172.1.
DR RefSeq; NP_031457.2; NM_007431.3.
DR RefSeq; XP_006538560.1; XM_006538497.3.
DR RefSeq; XP_006538561.1; XM_006538498.3.
DR RefSeq; XP_006538562.1; XM_006538499.3.
DR RefSeq; XP_006538563.1; XM_006538500.2.
DR RefSeq; XP_017175413.1; XM_017319924.1.
DR AlphaFoldDB; P09242; -.
DR SMR; P09242; -.
DR BioGRID; 198053; 7.
DR IntAct; P09242; 1.
DR STRING; 10090.ENSMUSP00000030551; -.
DR ChEMBL; CHEMBL2660; -.
DR GlyConnect; 2116; 2 N-Linked glycans (2 sites).
DR GlyGen; P09242; 5 sites, 2 N-linked glycans (2 sites).
DR iPTMnet; P09242; -.
DR PhosphoSitePlus; P09242; -.
DR SwissPalm; P09242; -.
DR CPTAC; non-CPTAC-3492; -.
DR jPOST; P09242; -.
DR MaxQB; P09242; -.
DR PaxDb; P09242; -.
DR PeptideAtlas; P09242; -.
DR PRIDE; P09242; -.
DR ProteomicsDB; 289876; -.
DR Antibodypedia; 2059; 1078 antibodies from 43 providers.
DR DNASU; 11647; -.
DR Ensembl; ENSMUST00000030551; ENSMUSP00000030551; ENSMUSG00000028766.
DR GeneID; 11647; -.
DR KEGG; mmu:11647; -.
DR UCSC; uc008vjr.3; mouse.
DR CTD; 249; -.
DR MGI; MGI:87983; Alpl.
DR VEuPathDB; HostDB:ENSMUSG00000028766; -.
DR eggNOG; KOG4126; Eukaryota.
DR GeneTree; ENSGT00950000183063; -.
DR HOGENOM; CLU_008539_4_0_1; -.
DR InParanoid; P09242; -.
DR OMA; RIMSKGM; -.
DR OrthoDB; 416703at2759; -.
DR PhylomeDB; P09242; -.
DR TreeFam; TF323513; -.
DR BRENDA; 3.1.3.1; 3474.
DR Reactome; R-MMU-163125; Post-translational modification: synthesis of GPI-anchored proteins.
DR SABIO-RK; P09242; -.
DR BioGRID-ORCS; 11647; 2 hits in 72 CRISPR screens.
DR ChiTaRS; Alpl; mouse.
DR PRO; PR:P09242; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; P09242; protein.
DR Bgee; ENSMUSG00000028766; Expressed in molar tooth and 212 other tissues.
DR ExpressionAtlas; P09242; baseline and differential.
DR Genevisible; P09242; MM.
DR GO; GO:0031225; C:anchored component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031012; C:extracellular matrix; IDA:MGI.
DR GO; GO:0065010; C:extracellular membrane-bounded organelle; IDA:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB.
DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0043262; F:adenosine-diphosphatase activity; IEA:RHEA.
DR GO; GO:0004035; F:alkaline phosphatase activity; IDA:MGI.
DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:RHEA.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0004427; F:inorganic diphosphatase activity; IEA:RHEA.
DR GO; GO:0050187; F:phosphoamidase activity; IDA:UniProtKB.
DR GO; GO:0052732; F:phosphoethanolamine phosphatase activity; ISO:MGI.
DR GO; GO:0033883; F:pyridoxal phosphatase activity; ISS:UniProtKB.
DR GO; GO:0016462; F:pyrophosphatase activity; IDA:UniProtKB.
DR GO; GO:0110148; P:biomineralization; IDA:MGI.
DR GO; GO:0030282; P:bone mineralization; IMP:UniProtKB.
DR GO; GO:0055074; P:calcium ion homeostasis; IDA:MGI.
DR GO; GO:0019725; P:cellular homeostasis; IMP:MGI.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:MGI.
DR GO; GO:0071529; P:cementum mineralization; IEA:Ensembl.
DR GO; GO:0016311; P:dephosphorylation; IBA:GO_Central.
DR GO; GO:0003006; P:developmental process involved in reproduction; IGI:MGI.
DR GO; GO:0001958; P:endochondral ossification; IMP:MGI.
DR GO; GO:0010259; P:multicellular organism aging; IMP:MGI.
DR GO; GO:0055062; P:phosphate ion homeostasis; IDA:MGI.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; IDA:UniProtKB.
DR GO; GO:0042822; P:pyridoxal phosphate metabolic process; IDA:UniProtKB.
DR GO; GO:0046677; P:response to antibiotic; IDA:MGI.
DR GO; GO:0051384; P:response to glucocorticoid; ISO:MGI.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:1904383; P:response to sodium phosphate; IDA:MGI.
DR GO; GO:0034516; P:response to vitamin B6; IMP:MGI.
DR GO; GO:0033280; P:response to vitamin D; IEA:Ensembl.
DR CDD; cd16012; ALP; 1.
DR Gene3D; 3.40.720.10; -; 1.
DR InterPro; IPR001952; Alkaline_phosphatase.
DR InterPro; IPR018299; Alkaline_phosphatase_AS.
DR InterPro; IPR017850; Alkaline_phosphatase_core_sf.
DR PANTHER; PTHR11596; PTHR11596; 1.
DR Pfam; PF00245; Alk_phosphatase; 1.
DR PRINTS; PR00113; ALKPHPHTASE.
DR SMART; SM00098; alkPPc; 1.
DR SUPFAM; SSF53649; SSF53649; 1.
DR PROSITE; PS00123; ALKALINE_PHOSPHATASE; 1.
PE 1: Evidence at protein level;
KW Biomineralization; Calcium; Cell membrane; Disulfide bond; Glycoprotein;
KW GPI-anchor; Hydrolase; Lipoprotein; Magnesium; Membrane; Metal-binding;
KW Mitochondrion; Phosphoprotein; Reference proteome; Signal; Zinc.
FT SIGNAL 1..17
FT CHAIN 18..501
FT /note="Alkaline phosphatase, tissue-nonspecific isozyme"
FT /id="PRO_0000024025"
FT PROPEP 502..524
FT /note="Removed in mature form"
FT /evidence="ECO:0000255"
FT /id="PRO_0000024026"
FT ACT_SITE 110
FT /note="Phosphoserine intermediate"
FT /evidence="ECO:0000250|UniProtKB:P05187,
FT ECO:0000255|PROSITE-ProRule:PRU10042"
FT BINDING 60
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 60
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 110
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 173
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 235
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P05186"
FT BINDING 290
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P05186"
FT BINDING 291
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P05186"
FT BINDING 306
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P05186"
FT BINDING 332
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 337
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 341
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 378
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 379
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT BINDING 454
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT MOD_RES 110
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT LIPID 501
FT /note="GPI-anchor amidated glycine"
FT /evidence="ECO:0000255"
FT CARBOHYD 140
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 230
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 271
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 303
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 430
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT DISULFID 139..201
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT DISULFID 489..497
FT /evidence="ECO:0000250|UniProtKB:P05187"
FT CONFLICT 521
FT /note="R -> P (in Ref. 1; AAA39928)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 524 AA; 57514 MW; 59D99110C60FA050 CRC64;
MISPFLVLAI GTCLTNSFVP EKERDPSYWR QQAQETLKNA LKLQKLNTNV AKNVIMFLGD
GMGVSTVTAA RILKGQLHHN TGEETRLEMD KFPFVALSKT YNTNAQVPDS AGTATAYLCG
VKANEGTVGV SAATERTRCN TTQGNEVTSI LRWAKDAGKS VGIVTTTRVN HATPSAAYAH
SADRDWYSDN EMPPEALSQG CKDIAYQLMH NIKDIDVIMG GGRKYMYPKN RTDVEYELDE
KARGTRLDGL DLISIWKSFK PRHKHSHYVW NRTELLALDP SRVDYLLGLF EPGDMQYELN
RNNLTDPSLS EMVEVALRIL TKNLKGFFLL VEGGRIDHGH HEGKAKQALH EAVEMDQAIG
KAGAMTSQKD TLTVVTADHS HVFTFGGYTP RGNSIFGLAP MVSDTDKKPF TAILYGNGPG
YKVVDGEREN VSMVDYAHNN YQAQSAVPLR HETHGGEDVA VFAKGPMAHL LHGVHEQNYI
PHVMAYASCI GANLDHCAWA GSGSAPSPGA LLLPLAVLSL RTLF
