Protein: Alkaline phosphatase, tissue-nonspecific isozyme (AP-TNAP) (TNAP) (TNSALP) (EC 3.1.3.1) (Alkaline phosphatase 2) (Alkaline phosphatase liver/bone/kidney isozyme) (Phosphoamidase) (Phosphocreatine phosphatase) (EC 3.9.1.1) (P09242)
Organism: Mus musculus (Mouse)
Function: Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis. 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. 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. 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. 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. 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. Additionally, also able to mediate ATP degradation in a stepwise manner to adenosine, thereby regulating the availability of ligands for purinergic receptors. 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) (By similarity). 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. 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.
Subcellular location: Cell membrane {ECO:0000250|UniProtKB:P05186}; Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P05186}. Extracellular vesicle membrane {ECO:0000269|PubMed:19874193, ECO:0000269|PubMed:23942722}; Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:33981039}. Mitochondrion membrane {ECO:0000269|PubMed:33981039}; Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:33981039}. Mitochondrion intermembrane space {ECO:0000269|PubMed:33981039}. Note=Localizes to special class of extracellular vesicles, named matrix vesicles (MVs), which are released by osteogenic cells (PubMed:19874193, PubMed:23942722). Localizes to the mitochondria of thermogenic fat cells: tethered to mitochondrial membranes via a GPI-anchor and probably resides in the mitochondrion intermembrane space (PubMed:33981039). {ECO:0000269|PubMed:19874193, ECO:0000269|PubMed:23942722, ECO:0000269|PubMed:33981039}.
Interaction partners:
- Thiamine pyrophosphokinase 1
- GTP cyclohydrolase 1
- 6-pyruvoyl tetrahydrobiopterin synthase
- Cancer-related nucleoside-triphosphatase homolog
- Runt-related transcription factor 2
- Osteocalcin
- Transcription factor Sp7
- Integrin-binding sialoprotein
- Collagen alpha-1
- Osteocalcin-2
Sequence:
MISPFLVLAIGTCLTNSFVPEKERDPSYWRQQAQETLKNALKLQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQLHHNTGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERTRCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEALSQGCKDIAYQLMHNIKDIDVIMGGGRKYMYPKNRTDVEYELDEKARGTRLDGLDLISIWKSFKPRHKHSHYVWNRTELLALDPSRVDYLLGLFEPGDMQYELNRNNLTDPSLSEMVEVALRILTKNLKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDQAIGKAGAMTSQKDTLTVVTADHSHVFTFGGYTPRGNSIFGLAPMVSDTDKKPFTAILYGNGPGYKVVDGERENVSMVDYAHNNYQAQSAVPLRHETHGGEDVAVFAKGPMAHLLHGVHEQNYIPHVMAYASCIGANLDHCAWAGSGSAPSPGALLLPLAVLSLRTLF