ALPL

There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue-nonspecific). The first three are located together on chromosome 2, whereas the tissue-nonspecific form is located on chromosome 1. The product of this gene is a membrane-bound glycosylated enzyme that is expressed in a variety of tissues and is, therefore, referred to as the tissue-nonspecific form of the enzyme. A proposed function of this form of the enzyme is in regulating matrix mineralization through its ability to degrade mineralization-inhibiting pyrophosphate. Mice that lack a functional form of this enzyme (gene knockout mice) show abnormal skeletal and dental development including a mineralization deficiency called osteomalacia/odontomalacia (hypomineralization of bones and teeth).{{cite journal | vauthors = McKee MD, Nakano Y, Masica DL, Gray JJ, Lemire I, Heft R, Whyte MP, Crine P, Millán JL | title = Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia | journal = Journal of Dental Research | volume = 90 | issue = 4 | pages = 470–476 | date = April 2011 | pmid = 21212313 | pmc = 3144124 | doi = 10.1177/0022034510393517 }}{{cite journal | vauthors = Millán JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP | title = Enzyme replacement therapy for murine hypophosphatasia | journal = Journal of Bone and Mineral Research | volume = 23 | issue = 6 | pages = 777–787 | date = June 2008 | pmid = 18086009 | pmc = 2652241 | doi = 10.1359/jbmr.071213 }}{{cite journal | vauthors = McKee MD, Hoac B, Addison WN, Barros NM, Millán JL, Chaussain C | title = Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia | journal = Periodontology 2000 | volume = 63 | issue = 1 | pages = 102–122 | date = October 2013 | pmid = 23931057 | pmc = 3766584 | doi = 10.1111/prd.12029 }}{{cite journal | vauthors = Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millán JL, MacGregor GR, Whyte MP | title = Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia | journal = Journal of Bone and Mineral Research | volume = 14 | issue = 12 | pages = 2015–2026 | date = December 1999 | pmid = 10620060 | pmc = 3049802 | doi = 10.1359/jbmr.1999.14.12.2015 }} Humans with inactivating mutations in the ALPL gene likewise have variable degrees of mineralization defects depending on the location of the mutation in the ALPL gene.{{cite journal | vauthors = Whyte MP | title = Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment | journal = Nature Reviews. Endocrinology | volume = 12 | issue = 4 | pages = 233–246 | date = April 2016 | pmid = 26893260 | doi = 10.1038/nrendo.2016.14 | s2cid = 20805434 }}{{cite journal | vauthors = Whyte MP | title = Hypophosphatasia: An overview For 2017 | journal = Bone | volume = 102 | pages = 15–25 | date = September 2017 | pmid = 28238808 | doi = 10.1016/j.bone.2017.02.011 }}

Tissue Non-Specific Alkaline Phosphatase (TNAP), encoded by the ALPL gene, exhibits an intriguing octameric structure as revealed by X-ray crystallography.{{cite journal | vauthors = Yu Y, Rong K, Yao D, Zhang Q, Cao X, Rao B, Xia Y, Lu Y, Shen Y, Yao Y, Xu H, Ma P, Cao Y, Qin A |date=2023-07-08 |title=The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase |journal=Nature Communications |language=en |volume=14 |issue=1 |pages=4048 |doi=10.1038/s41467-023-39833-3 | pmid = 37422472 |issn=2041-1723|pmc=10329691 | bibcode = 2023NatCo..14.4048Y }} This distinct arrangement consists of four individual dimeric TNAP units. Structural studies on homologs of TNAP, namely human (ALPP){{cite journal | vauthors = Le Du MH, Stigbrand T, Taussig MJ, Menez A, Stura EA | title = Crystal structure of alkaline phosphatase from human placenta at 1.8 A resolution. Implication for a substrate specificity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9158–9165 | date = March 2001 | pmid = 11124260 | doi = 10.1074/jbc.M009250200 | doi-access = free }} and Escherichia coli (ecPhoA),{{cite journal | vauthors = Kim EE, Wyckoff HW | title = Reaction mechanism of alkaline phosphatase based on crystal structures. Two-metal ion catalysis | journal = Journal of Molecular Biology | volume = 218 | issue = 2 | pages = 449–464 | date = March 1991 | pmid = 2010919 | doi = 10.1016/0022-2836(91)90724-K }} have identified the dimer as the minimal stable unit of TNAP. Notably, a single TNAP protein contains four metal ion binding sites: two Zn²⁺ sites and one Mg²⁺ site situated in the reaction center, and one Ca2+ site within the regulatory pocket. The octameric state observed in TNAP is unique compared to previously characterized alkaline phosphatases, all of which have been found in a dimeric state.

As the isozyme name “tissue-nonspecific” implies, TNAP is expressed ubiquitously and modified by post-translational glycosylation processes, to become isoforms{{cite journal | vauthors = Haarhaus M, Cianciolo G, Barbuto S, La Manna G, Gasperoni L, Tripepi G, Plebani M, Fusaro M, Magnusson P | title = Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease | journal = Nutrients | volume = 14 | issue = 10 | pages = 2124 | date = May 2022 | pmid = 35631265 | pmc = 9144546 | doi = 10.3390/nu14102124 | doi-access = free }} that provide significant proteomic diversity and specificity relating to various tissues and cells. The highest levels of human TNAP isoforms are expressed in bone, liver, and kidney tissues, with neutrophil granulocytes, brain and vascular cells as secondary sources of TNAP activity.

In human serum, the bone ALP (BALP) and liver ALP isoforms are the most abundant TNAP isoforms, in approximately a 1:1 ratio, comprising more than 90% of the total ALP activity. The remaining circulating ALP activity, 1–10%, is attributed mostly to intestinal ALP (IALP).

Several different analytical methods for separation and quantification of serum ALP isozymes and TNAP isoforms have been described over the years. Separation techniques like electrophoresis and chromatography are valuable for studying enzymes and proteins, revealing insights into their structure and function in pharmaceutical research and post-translational modifications (PTM) studies.{{Cite journal | vauthors = Balbaied T, Moore E |date=2023-09-15 |title=Overview of Capillary Electrophoresis Analysis of Alkaline Phosphatase (ALP) with Emphasis on Post-Translational Modifications (PTMs) |journal=Kinases and Phosphatases |language=en |volume=1 |issue=3 |pages=206–219 |doi=10.3390/kinasesphosphatases1030013 |doi-access=free |issn=2813-3757}} In particular, the development of commercial immunoassays for serum ALP has improved the usefulness and availability for clinical routine and research.

This enzyme has been linked directly to a disorder known as hypophosphatasia, a disorder that is characterized by low serum ALP and undermineralised bone (osteomalacia). The character of this disorder can vary, however, depending on the specific mutation, since this determines age of onset and severity of symptoms.

The severity of symptoms ranges from premature loss of deciduous teeth with no bone abnormalities to stillbirth{{cite journal | vauthors = Hérasse M, Spentchian M, Taillandier A, Mornet E | title = Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients | journal = European Journal of Human Genetics | volume = 10 | issue = 10 | pages = 666–668 | date = October 2002 | pmid = 12357339 | doi = 10.1038/sj.ejhg.5200857 | doi-access = free }} depending upon which amino acid{{cite journal | vauthors = Nasu M, Ito M, Ishida Y, Numa N, Komaru K, Nomura S, Oda K | title = Aberrant interchain disulfide bridge of tissue-nonspecific alkaline phosphatase with an Arg433→Cys substitution associated with severe hypophosphatasia | journal = The FEBS Journal | volume = 273 | issue = 24 | pages = 5612–5624 | date = December 2006 | pmid = 17212778 | doi = 10.1093/oxfordjournals.jbchem.a022032 }}{{cite journal | vauthors = Ishida Y, Komaru K, Ito M, Amaya Y, Kohno S, Oda K | title = Tissue-nonspecific alkaline phosphatase with an Asp(289)→Val mutation fails to reach the cell surface and undergoes proteasome-mediated degradation | journal = Journal of Biochemistry | volume = 134 | issue = 1 | pages = 63–70 | date = July 2003 | pmid = 12944372 | doi = 10.1093/jb/mvg114 }} is changed in the ALPL gene. Mutations in the ALPL gene lead to varying low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP or TNAP) resulting in hypophosphatasia (HPP).{{cite journal | vauthors = Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millán JL, MacGregor GR, Whyte MP | title = Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia | journal = Journal of Bone and Mineral Research | volume = 14 | issue = 12 | pages = 2015–2026 | date = December 1999 | pmid = 10620060 | pmc = 3049802 | doi = 10.1359/jbmr.1999.14.12.2015 }} There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait, the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth. ALPL gene mutation leads to insufficient TNAP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate to indirectly cause elevated calcium levels in the body and lack of bone calcification.

The mutation E174K, where a glycine is converted to an alanine amino acid at the 571st position of its respective polypeptide chain, is a result of an ancestral mutation that occurred in Caucasians and shows a mild form of HPP.

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• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hops GeneReviews/NCBI/NIH/UW entry on Hypophosphatasia]
• {{UCSC gene info|ALPL}}

{{Esterases}}

Category:Enzymes