ALPL

Last updated

ALPL
Human ALPL octamer.png
Identifiers
Aliases ALPL , AP-TNAP, APTNAP, HOPS, TNAP, TNSALP, alkaline phosphatase, liver/bone/kidney, TNALP, alkaline phosphatase, biomineralization associated, HPPA, HPPI, HPPC, HPPO, TNS-ALP
External IDs OMIM: 171760; MGI: 87983; HomoloGene: 37314; GeneCards: ALPL; OMA:ALPL - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001287172
NM_001287176
NM_007431

RefSeq (protein)

NP_001274101
NP_031457

Location (UCSC) Chr 1: 21.51 – 21.58 Mb Chr 4: 137.47 – 137.52 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Alkaline phosphatase, tissue-nonspecific isozyme (TNAP) is an enzyme that in humans is encoded by the ALPL gene. [5] [6]

Contents

TNAP catalyses the breakdown of pyrophosphate (an extracellular inhibitor of hydroxyapatite precipitation). It is secreted into the osteoid by osteoblasts to allow bone mineralization to take place. [7]

Function

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). [8] [9] [10] [11] 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. [12] [13]

Structure

Tissue Non-Specific Alkaline Phosphatase (TNAP), encoded by the ALPL gene, exhibits an intriguing octameric structure as revealed by X-ray crystallography. [14] This distinct arrangement consists of four individual dimeric TNAP units. Structural studies on homologs of TNAP, namely human (ALPP) [15] and Escherichia coli (ecPhoA), [16] 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.

Tissue expression and isoforms

As the isozyme name “tissue-nonspecific” implies, TNAP is expressed ubiquitously and modified by post-translational glycosylation processes, to become isoforms [17] 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. [18] In particular, the development of commercial immunoassays for serum ALP has improved the usefulness and availability for clinical routine and research.

Clinical significance

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 [19] depending upon which amino acid [20] [21] 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). [22] There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait, [19] the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth. [22] ALPL gene mutation leads to insufficient TNAP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate [22] 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. [19]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162551 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028766 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Weiss MJ, Henthorn PS, Lafferty MA, Slaughter C, Raducha M, Harris H (October 1986). "Isolation and characterization of a cDNA encoding a human liver/bone/kidney-type alkaline phosphatase". Proceedings of the National Academy of Sciences of the United States of America. 83 (19): 7182–7186. Bibcode:1986PNAS...83.7182W. doi: 10.1073/pnas.83.19.7182 . PMC   386679 . PMID   3532105.
  6. Swallow DM, Povey S, Parkar M, Andrews PW, Harris H, Pym B, et al. (July 1986). "Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1". Annals of Human Genetics. 50 (3): 229–235. doi:10.1111/j.1469-1809.1986.tb01043.x. PMID   3446011. S2CID   20363222.
  7. Hall JE, Hall ME (2021). "Chapter 55 - Spinal Cord Motor Functions; the Cord Reflexes". Guyton and Hall Textbook of Medical Physiology (14th ed.). Philadelphia, PA: Elsevier. pp. 994–995. ISBN   978-0-323-59712-8.
  8. McKee MD, Nakano Y, Masica DL, Gray JJ, Lemire I, Heft R, et al. (April 2011). "Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia". Journal of Dental Research. 90 (4): 470–476. doi:10.1177/0022034510393517. PMC   3144124 . PMID   21212313.
  9. Millán JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, et al. (June 2008). "Enzyme replacement therapy for murine hypophosphatasia". Journal of Bone and Mineral Research. 23 (6): 777–787. doi:10.1359/jbmr.071213. PMC   2652241 . PMID   18086009.
  10. McKee MD, Hoac B, Addison WN, Barros NM, Millán JL, Chaussain C (October 2013). "Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia". Periodontology 2000. 63 (1): 102–122. doi:10.1111/prd.12029. PMC   3766584 . PMID   23931057.
  11. Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, et al. (December 1999). "Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia". Journal of Bone and Mineral Research. 14 (12): 2015–2026. doi:10.1359/jbmr.1999.14.12.2015. PMC   3049802 . PMID   10620060.
  12. Whyte MP (April 2016). "Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment". Nature Reviews. Endocrinology. 12 (4): 233–246. doi:10.1038/nrendo.2016.14. PMID   26893260. S2CID   20805434.
  13. Whyte MP (September 2017). "Hypophosphatasia: An overview For 2017". Bone. 102: 15–25. doi:10.1016/j.bone.2017.02.011. PMID   28238808.
  14. Yu Y, Rong K, Yao D, Zhang Q, Cao X, Rao B, et al. (2023-07-08). "The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase". Nature Communications. 14 (1): 4048. Bibcode:2023NatCo..14.4048Y. doi:10.1038/s41467-023-39833-3. ISSN   2041-1723. PMC   10329691 . PMID   37422472.
  15. Le Du MH, Stigbrand T, Taussig MJ, Menez A, Stura EA (March 2001). "Crystal structure of alkaline phosphatase from human placenta at 1.8 A resolution. Implication for a substrate specificity". The Journal of Biological Chemistry. 276 (12): 9158–9165. doi: 10.1074/jbc.M009250200 . PMID   11124260.
  16. Kim EE, Wyckoff HW (March 1991). "Reaction mechanism of alkaline phosphatase based on crystal structures. Two-metal ion catalysis". Journal of Molecular Biology. 218 (2): 449–464. doi:10.1016/0022-2836(91)90724-K. PMID   2010919.
  17. Haarhaus M, Cianciolo G, Barbuto S, La Manna G, Gasperoni L, Tripepi G, et al. (May 2022). "Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease". Nutrients. 14 (10): 2124. doi: 10.3390/nu14102124 . PMC   9144546 . PMID   35631265.
  18. Balbaied T, Moore E (2023-09-15). "Overview of Capillary Electrophoresis Analysis of Alkaline Phosphatase (ALP) with Emphasis on Post-Translational Modifications (PTMs)". Kinases and Phosphatases. 1 (3): 206–219. doi: 10.3390/kinasesphosphatases1030013 . ISSN   2813-3757.
  19. 1 2 3 Hérasse M, Spentchian M, Taillandier A, Mornet E (October 2002). "Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients". European Journal of Human Genetics. 10 (10): 666–668. doi: 10.1038/sj.ejhg.5200857 . PMID   12357339.
  20. Nasu M, Ito M, Ishida Y, Numa N, Komaru K, Nomura S, et al. (December 2006). "Aberrant interchain disulfide bridge of tissue-nonspecific alkaline phosphatase with an Arg433→Cys substitution associated with severe hypophosphatasia". The FEBS Journal. 273 (24): 5612–5624. doi:10.1093/oxfordjournals.jbchem.a022032. PMID   17212778.
  21. Ishida Y, Komaru K, Ito M, Amaya Y, Kohno S, Oda K (July 2003). "Tissue-nonspecific alkaline phosphatase with an Asp(289)→Val mutation fails to reach the cell surface and undergoes proteasome-mediated degradation". Journal of Biochemistry. 134 (1): 63–70. doi:10.1093/jb/mvg114. PMID   12944372.
  22. 1 2 3 Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, et al. (December 1999). "Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia". Journal of Bone and Mineral Research. 14 (12): 2015–2026. doi:10.1359/jbmr.1999.14.12.2015. PMC   3049802 . PMID   10620060.

Further reading