ArticlePloS one2015
Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 46 citations in OpenAlex.
- Article
- Hypophosphatasia-pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Review
- Review
- Synthesis and Characterization of a Strontium-Quercetin Complex and Its In Vitro and In Vivo Potential for Application in Bone Regeneration.ACS omega · 2025Article
- Zinc-alkaline phosphatase at sites of aortic calcification.Journal of molecular histology · 2024Article
- Bone resorption and formation in the pedicles of European roe deer (Capreolus capreolus) in relation to the antler cycle-A morphological and microanalytical study.Journal of anatomy · 2023Article
- ADRA1A-GαNature metabolism · 2022Article
- Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease.Nutrients · 2022Review
- TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body.Cardiovascular research · 2022Review
- Characterization of Genetic Variants of Uncertain Significance for theFrontiers in endocrinology · 2022Article
- Hypophosphatasia: A Unique Disorder of Bone Mineralization.International journal of molecular sciences · 2021Review
- TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism.International journal of molecular sciences · 2021Review
- Effect of Magnesium on Dentinogenesis of Human Dental Pulp Cells.International journal of biomaterials · 2021Article
- Tissue-Nonspecific Alkaline Phosphatase-A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease.Biomolecules · 2020Review
- Combination Antitumor Effect of Sorafenib via Calcium-Dependent Deactivation of Focal Adhesion Kinase Targeting Colorectal Cancer Cells.Molecules (Basel, Switzerland) · 2020Article
- Matrix vesicle biomimetics harboring Annexin A5 and alkaline phosphatase bind to the native collagen matrix produced by mineralizing vascular smooth muscle cells.Biochimica et biophysica acta. General subjects · 2020Article
- Quantitative atomic force microscopy provides new insight into matrix vesicle mineralization.Archives of biochemistry and biophysics · 2019Article
- Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD.Nature reviews. Nephrology · 2017Review
- Human alkaline phosphatase dephosphorylates microbial products and is elevated in preterm neonates with a history of late-onset sepsis.PloS one · 2017Article
- Alkaline Phosphatase and Hypophosphatasia.Calcified tissue international · 2016Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
The conserved active site of alkaline phosphatases (AP) contains catalytically important Zn2+ (M1 and M2) and Mg2+-sites (M3) and a fourth peripheral Ca2+ site (M4) of unknown significance. We have studied Ca2+ binding to M1-4 of tissue-nonspecific AP (TNAP), an enzyme crucial for skeletal mineralization, using recombinant TNAP and a series of M4 mutants. Ca2+ could substitute for Mg2+ at M3, with maximal activity for Ca2+/Zn2+-TNAP around 40% that of Mg2+/Zn2+-TNAP at pH 9.8 and 7.4. At pH 7.4, allosteric TNAP-activation at M3 by Ca2+ occurred faster than by Mg2+. Several TNAP M4 mutations eradicated TNAP activity, while others mildly influenced the affinity of Ca2+ and Mg2+ for M3 similarly, excluding a catalytic role for Ca2+ in the TNAP M4 site. At pH 9.8, Ca2+ competed with soluble Zn2+ for binding to M1 and M2 up to 1 mM and at higher concentrations, it even displaced M1- and M2-bound Zn2+, forming Ca2+/Ca2+-TNAP with a catalytic activity only 4-6% that of Mg2+/Zn2+-TNAP. At pH 7.4, competition with Zn2+ and its displacement from M1 and M2 required >10-fold higher Ca2+ concentrations, to generate weakly active Ca2+/Ca2+-TNAP. Thus, in a Ca2+-rich environment, such as during skeletal mineralization at pH 7.4, Ca2+ adequately activates Zn2+-TNAP at M3, but very high Ca2+ concentrations compete with available Zn2+ for binding to M1 and M2 and ultimately displace Zn2+ from the active site, virtually inactivating TNAP. Those ALPL mutations that substitute critical TNAP amino acids involved in coordinating Ca2+ to M4 cause hypophosphatasia because of their 3D-structural impact, but M4-bound Ca2+ is catalytically inactive. In conclusion, during skeletal mineralization, the building Ca2+ gradient first activates TNAP, but gradually inactivates it at high Ca2+ concentrations, toward completion of mineralization.
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