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.
Highlights
Alkaline phosphatases are specific enzymes present in most living organisms catalyzing the dephosphorylation of pyrophosphate (PPi) and pyridoxal-5 -phosphate (PLP) in vivo, presumably as well as nucleotides like ATP and proteins like osteopontin [1,2,3]
The current level of knowledge implies that Tissue-nonspecific alkaline phosphatase (TNAP) is involved in a wide number of molecular and biochemical processes and thereby acts as an important gatekeeper of physiological conditions in health
Like the rare disease HPP, TNAP deficiency can lead to a prominent skeletal phenotype as well as a multisystemic disorder affecting muscles, kidneys, lung, teeth, and the nervous system
Summary
Humans have four different genes encoding distinct alkaline phosphatase isoforms [4]. According to ENSEMBL and MGI databases, mice have five different genes coding for alkaline phosphatases, as the tissue-nonspecific isoform is encoded by the gene Alpl/Akp (ENSMUSG00000028766, MGI: 87983), and Akp (ENSMUSG00000036500, MGI: 87984), Alppl (ENSMUSG00000026246, MGI: 108009), Akp (NCBI Gene ID: 109899, MGI: 87982, not included in current mouse ENSEMBL genome annotation release), and Alpi (ENSMUSG00000079440, MGI: 1924018) are prevalent. The human ALPL gene is located on chromosome 1 and encodes, according to the ENSEMBL database, seven different transcripts (for details, see ENSG00000162551), including predicted transcripts, which are not protein-coding and have not been analyzed in full detail. The murine Alpl gene is located on chromosome 4, encodes 8 different ENSEMBL database transcripts, while the reference transcript (ENSMUST00000030551.10; CCDS18821) contains overall exons, coding exons, and has a transcript length of 2522 bp. The zebrafish ENSEMBL database reference alpl transcript (ENSDART00000146461.3) contains exons that are all coding and has a transcript length of 1871 bp (genome assembly: GRCh38.p13, GRCm38.p6, GRCz11; summarized in [7] and [8])
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