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Alpl

Developmental stage

Not expressed prior to gastrulation in embryo, while it is expressed before in extraembryonic lineage cells destined to form the chorion (PubMed:7789278). Expressed in both embryonic and extraembryonic lineages during embryogenesis (PubMed:7789278). Expressed in early bell stage dental mesenchymal cells at 15.5 dpc (at protein level) (PubMed:24028588). Expressed in bell stage dental mesenchymal cells at 17.5 dpc (PubMed:29148101).

Domain

Calcium-binding is structural and does not influence the alkaline phosphatase activity. At very high concentrations, calcium can however substitute for zinc at zinc-binding sites, leading to strongly reduced enzyme activity.

Function

Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis (PubMed:10620060, PubMed:11028439, PubMed:14982838, PubMed:23942722, PubMed:33981039). 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:19874193, PubMed:23942722, PubMed:33981039). 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:10620060, PubMed:11004006, PubMed:11028439, PubMed:12082181, PubMed:14982838, PubMed:32035618, PubMed:9056646). 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 (PubMed:20684022, PubMed:26457330). 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 (PubMed:23427088). 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:7550313). Additionally, also able to mediate ATP degradation in a stepwise manner to adenosine, thereby regulating the availability of ligands for purinergic receptors (PubMed:19874193, PubMed:23825434, PubMed:23942722, PubMed:32028019). 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 (PubMed:33981039). 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 (PubMed:33981039).

Post-translational modifications

N-glycosylated.

Sequence Similarities

Belongs to the alkaline phosphatase family.

Tissue Specificity

Widely expressed (PubMed:3478679). Expressed in DRG neurons and spinal cord neurons (PubMed:23825434).

Cellular localization

Alternative names

Akp-2, Akp2, Alpl, AP-TNAP, TNAP, TNSALP, Alkaline phosphatase 2, Alkaline phosphatase liver/bone/kidney isozyme, Phosphoamidase, Phosphocreatine phosphatase

swissprot:P09242 entrezGene:11647 swissprot:P24822 entrezGene:76768