{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P05186","secondaryAccessions":["A1A4E7","B2RMP8","B7Z387","B7Z4Y6","O75090","Q2TAI7","Q59EJ7","Q5BKZ5","Q5VTG5","Q6NZI8","Q8WU32","Q9UBK0"],"uniProtkbId":"PPBT_HUMAN","entryAudit":{"firstPublicDate":"1987-08-13","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2005-06-21","entryVersion":257,"sequenceVersion":4},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"2220817"}],"value":"Alkaline phosphatase, tissue-nonspecific isozyme"},"shortNames":[{"value":"AP-TNAP"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"2220817"}],"value":"TNS-ALP"},{"value":"TNSALP"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2220817"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23039266"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23688511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25982064"}],"value":"3.1.3.1"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"3532105"}],"value":"Alkaline phosphatase liver/bone/kidney isozyme"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Phosphoamidase"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Phosphocreatine phosphatase"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"3.9.1.1"}]}],"flag":"Precursor"},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"8406453"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:438"}],"value":"ALPL"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12162492"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20049532"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2220817"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23688511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25982064"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28448526"}],"value":"Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis (PubMed:12162492, PubMed:23688511, PubMed:25982064). Has broad substrate specificity and can hydrolyze a considerable variety of compounds: however, only a few substrates, such as diphosphate (inorganic pyrophosphate; PPi), pyridoxal 5'-phosphate (PLP) and N-phosphocreatine are natural substrates (PubMed:12162492, PubMed:2220817). Plays an essential role in skeletal and dental mineralization via its ability to hydrolyze extracellular diphosphate, a potent mineralization inhibitor, to phosphate: it thereby promotes hydroxyapatite crystal formation and increases inorganic phosphate concentration (PubMed:23688511, PubMed:25982064). Acts in a non-redundant manner with PHOSPHO1 in skeletal mineralization: while PHOSPHO1 mediates the initiation of hydroxyapatite crystallization in the matrix vesicles (MVs), ALPL/TNAP catalyzes the spread of hydroxyapatite crystallization in the extracellular matrix (By similarity). Also promotes dephosphorylation of osteopontin (SSP1), an inhibitor of hydroxyapatite crystallization in its phosphorylated state; it is however unclear whether ALPL/TNAP mediates SSP1 dephosphorylation via a direct or indirect manner (By similarity). Catalyzes dephosphorylation of PLP to pyridoxal (PL), the transportable form of vitamin B6, in order to provide a sufficient amount of PLP in the brain, an essential cofactor for enzymes catalyzing the synthesis of diverse neurotransmitters (PubMed:20049532, PubMed:2220817). Additionally, also able to mediate ATP degradation in a stepwise manner to adenosine, thereby regulating the availability of ligands for purinergic receptors (By similarity). Also capable of dephosphorylating microbial products, such as lipopolysaccharides (LPS) as well as other phosphorylated small-molecules, such as poly-inosine:cytosine (poly I:C) (PubMed:28448526). Acts as a key regulator of adaptive thermogenesis as part of the futile creatine cycle: localizes to the mitochondria of thermogenic fat cells and acts by mediating hydrolysis of N-phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation (By similarity). During the futile creatine cycle, creatine and N-phosphocreatine are in a futile cycle, which dissipates the high energy charge of N-phosphocreatine as heat without performing any mechanical or chemical work (By similarity)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a phosphate monoester + H2O = an alcohol + 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REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23688511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25982064"}],"value":"Homodimer"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Localizes to special class of extracellular vesicles, named matrix vesicles (MVs), which are released by osteogenic cells. Localizes to the mitochondria of thermogenic fat cells: tethered to mitochondrial membranes via a GPI-anchor and probably resides in the mitochondrion intermembrane space"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2220817"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23688511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25982064"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33821301"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23688511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25982064"}],"value":"Lipid-anchor, GPI-anchor","id":"SL-9902"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Extracellular vesicle membrane","id":"SL-0500"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Lipid-anchor, GPI-anchor","id":"SL-9902"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Mitochondrion membrane","id":"SL-0171"},"topology":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Lipid-anchor, GPI-anchor","id":"SL-9902"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P09242"}],"value":"Mitochondrion intermembrane space","id":"SL-0169"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["P05186-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["P05186-2"],"sequenceIds":["VSP_042711"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["P05186-3"],"sequenceIds":["VSP_044228"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25775211"}],"value":"Calcium-binding is structural and does not influence the alkaline phosphatase activity (PubMed:25775211). At very high concentrations, calcium can however substitute for zinc at zinc-binding sites, leading to strongly reduced enzyme activity (PubMed:25775211)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1458595"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19159218"}],"value":"N-glycosylated"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Hypophosphatasia","diseaseAccession":"DI-01796","acronym":"HOPS","description":"A metabolic bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Four forms are distinguished, depending on the age of onset: perinatal, infantile, childhood and adult type. The perinatal form is the most severe and is almost always fatal. The adult form is mild and characterized by recurrent fractures, osteomalacia, rickets, and loss of teeth. Some cases are asymptomatic, while some patients manifest dental features without skeletal manifestations (odontohypophosphatasia).","diseaseCrossReference":{"database":"MIM","id":"146300"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10094560"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10332035"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10679946"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10690885"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10834525"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11395499"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11438998"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11479741"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11745997"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11760847"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11834095"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11855933"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11999978"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12162492"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12230456"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12815606"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12920074"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1409720"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15135428"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15694177"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19500388"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20049532"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22266140"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23039266"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23688511"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23791648"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25982064"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30083035"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"3174660"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32983484"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33821301"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7833929"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8406453"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8954059"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9452105"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9747027"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9781036"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Hypophosphatasia, childhood","diseaseAccession":"DI-03098","acronym":"HPPC","description":"A bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase.","diseaseCrossReference":{"database":"MIM","id":"241510"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11760847"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Hypophosphatasia, infantile","diseaseAccession":"DI-03099","acronym":"HPPI","description":"A severe bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Three more or less distinct types of infantile hypophosphatasia can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe 'rachitic' skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies.","diseaseCrossReference":{"database":"MIM","id":"241500"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10834525"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11438998"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12162492"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7833929"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8954059"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this 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