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Physiological role of alkaline phosphatase explored in hypophosphatasia
Author(s) -
Whyte Michael P.
Publication year - 2010
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2010.05387.x
Subject(s) - hypophosphatasia , alkaline phosphatase , osteomalacia , chemistry , pyrophosphate , rickets , biochemistry , endocrinology , medicine , pyrophosphatase , enzyme , biology , vitamin d and neurology
Hypophosphatasia (HPP) is the instructive rickets or osteomalacia caused by loss‐of‐function mutation(s) within TNSALP , the gene that encodes the “tissue nonspecific” isoenzyme of alkaline phosphatase (TNSALP). HPP reveals a critical role for this enzyme in skeletal mineralization. Increased extracellular levels of pyridoxal 5′‐phosphate and inorganic pyrophosphate (PP i ) demonstrate that TNSALP is a phosphomonoester phosphohydrolase and a pyrophosphatase that hydrolyzes much lower concentrations of natural substrates than the artificial substrates of laboratory assays. Clearly, TNSALP acts at physiological pH and “alkaline phosphatase” is a misnomer. Aberrations of vitamin B 6 metabolism in HPP revealed that TNSALP is an ectoenzyme. PP i excesses cause chondrocalcinosis and sometimes arthropathy. The skeletal disease is due to PP i inhibition of hydroxyapatite crystal growth extracellularly so that crystals form within matrix vesicles but fail to enlarge after these structures rupture. Trials of alkaline phosphatase replacement therapy for HPP suggest that TNSALP functions at the level of skeletal tissues.