9sh5

Structural highlights

Disease

PPBT_HUMAN Prenatal benign hypophosphatasia;Adult hypophosphatasia;Perinatal lethal hypophosphatasia;Childhood-onset hypophosphatasia;Infantile hypophosphatasia;Odontohypophosphatasia. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

PPBT_HUMAN 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).[UniProtKB:P09242]^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Di Mauro S, Manes T, Hessle L, Kozlenkov A, Pizauro JM, Hoylaerts MF, Millán JL. Kinetic characterization of hypophosphatasia mutations with physiological substrates. J Bone Miner Res. 2002 Aug;17(8):1383-91. PMID:12162492 doi:10.1359/jbmr.2002.17.8.1383
2. ↑ Balasubramaniam S, Bowling F, Carpenter K, Earl J, Chaitow J, Pitt J, Mornet E, Sillence D, Ellaway C. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5'-phosphate availability. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S25-33. PMID:20049532 doi:10.1007/s10545-009-9012-y
3. ↑ Fedde KN, Whyte MP. Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5'-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study. Am J Hum Genet. 1990 Nov;47(5):767-75 PMID:2220817
4. ↑ Sultana S, Al-Shawafi HA, Makita S, Sohda M, Amizuka N, Takagi R, Oda K. An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. Mol Genet Metab. 2013 Jul;109(3):282-8. PMID:23688511 doi:10.1016/j.ymgme.2013.04.016
5. ↑ Numa-Kinjoh N, Komaru K, Ishida Y, Sohda M, Oda K. Molecular phenotype of tissue-nonspecific alkaline phosphatase with a proline (108) to leucine substitution associated with dominant odontohypophosphatasia. Mol Genet Metab. 2015 Aug;115(4):180-5. PMID:25982064 doi:10.1016/j.ymgme.2015.05.006
6. ↑ Pettengill M, Matute JD, Tresenriter M, Hibbert J, Burgner D, Richmond P, Millán JL, Ozonoff A, Strunk T, Currie A, Levy O. Human alkaline phosphatase dephosphorylates microbial products and is elevated in preterm neonates with a history of late-onset sepsis. PLoS One. 2017 Apr 27;12(4):e0175936. PMID:28448526 doi:10.1371/journal.pone.0175936