Tissue-Nonspecific Alkaline Phosphatase-A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5'-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme's role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

Keywords: ALPL; HPP; TNAP; craniosynostosis; hypophosphatasia; mineralization; nervous system; teeth; zebrafish.

Figure 1

Potential enzymatic functions and structural visualization of TNAP. (A) Depiction of potential TNAP substrates. (B) Schematic depiction of a predicted homology model of TNAP’s dimerized 3D structure (https://swissmodel.expasy.org/; SWISS-MODEL: P05186 (PPBT_HUMAN); homology model according to the template: 3mk1.1.B “Refinement of placental alkaline phosphatase complexed with nitrophenyl”) and magnified view of the active site [26,27,28]. Figure 1B was modified according to SWISS-MODEL database terms of use and is licensed under a Creative Commons Attribution 4.0 (https://creativecommons.org/licenses/by-sa/4.0/). ATP/ADP/AMP: adenosine tri-/di-/monophosphate, GPI-anchor: glycosyl-phosphatidylinositol anchor, Pi: phosphate, PLP: pyridoxal-5′-phosphate, p-OPN: phosphorylated osteopontin, PPi: inorganic pyrophosphate, TNAP: tissue-nonspecific alkaline phosphatase.

Figure 2

Schematic model of TNAP function within mineralizing cells (Modified according to Yadav et al. 2014 [67]). ATP: adenosine triphosphate, ANKH: progressive ankylosis protein homolog, ENPP1: ectonucleotide pyrophosphatase/ phosphodiesterase family member 1, SPP1/OPN: secreted phosphoprotein 1/osteopontin, Phospho1: phosphoethanolamine/phosphocholine phosphatase, Pi: Phosphate, PiT-1/2: sodium-dependent phosphate transporters 1 and 2, p-OPN: phosphorylated osteopontin, PPi: inorganic pyrophosphate, TNAP: tissue-nonspecific alkaline phosphatase.

Figure 3

The role of TNAP within the purinergic signaling. ATP/ADP/AMP: adenosine tri-/die-/monophosphate, cAMP: cyclic adenosine monophosphate, DAG: diacylglycerol, CD39/ENTPDase1: ectonucleoside triphosphate diphosphohydrolase 1, IP₃: Inositol trisphosphate, CD73/NT5E: ecto-5′-nucleotidase, PIP₂: phosphatidylinositol 4,5-bisphosphate, PKA: phosphokinase A, PLC: phospholipase C, TNAP: tissue-nonspecific alkaline phosphatase.

Figure 4

TNAP function is linked to PLP/cofactor, neurotrophic factor and myelin synthesis. (A) TNAP’s influence on the GABA synthesis. (B) TNAP’s role in the catecholamine and serotonin synthesis. (C) TNAP’s impact on purinergic signaling. (D) TNAP’s role in the myelin synthesis pathway. HTP: 5-hydroxytryptophan, AADC: aromatic L-amino acid decarboxylase, ATP/ADP/AMP: adenosine tri-/di-/monophosphate, BBB: blood–brain barrier, GABA: gamma-aminobutyric acid, GAD: glutamate decarboxylase, L-DOPA: levodopa, PDXK: pyridoxal kinase, PLP: pyridoxal-5′-phosphate, TNAP: tissue-nonspecific alkaline phosphatase.