Biology:ALPL

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Short description: Protein-coding gene in the species Homo sapiens

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.[1][2]

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).[3][4][5][6] 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.[7][8]

Structure

Tissue Non-Specific Alkaline Phosphatase (TNAP), encoded by the ALPL gene, exhibits an intriguing octameric structure as revealed by X-ray crystallography.[9] This distinct arrangement consists of four individual dimeric TNAP units. Structural studies on homologs of TNAP, namely human (ALPP)[10] and Escherichia coli (ecPhoA),[11] 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.

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[12] depending upon which amino acid[13][14] is changed in the ALPL gene. Mutations in the ALPL gene lead to varying low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP) resulting in hypophosphatasia (HPP).[15] There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait,[12] the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth.[15] ALPL gene mutation leads to insufficient TNSALP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate[15] 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.[12]

References

  1. ↑ "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. October 1986. doi:10.1073/pnas.83.19.7182. PMID 3532105. Bibcode: 1986PNAS...83.7182W. 
  2. ↑ "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. July 1986. doi:10.1111/j.1469-1809.1986.tb01043.x. PMID 3446011. 
  3. ↑ McKee, M. D.; Nakano, Y.; Masica, D. L.; Gray, J. J.; Lemire, I.; Heft, R.; Whyte, M. P.; Crine, P. et al. (2011). "Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia". Journal of Dental Research 90 (4): 470–476. doi:10.1177/0022034510393517. PMID 21212313. 
  4. ↑ Millán, J. L.; Narisawa, S.; Lemire, I.; Loisel, T. P.; Boileau, G.; Leonard, P.; Gramatikova, S.; Terkeltaub, R. et al. (2008). "Enzyme replacement therapy for murine hypophosphatasia". Journal of Bone and Mineral Research 23 (6): 777–787. doi:10.1359/jbmr.071213. PMID 18086009. 
  5. ↑ McKee, M. D.; Hoac, B.; Addison, W. N.; Barros, N. M.; Millán, J. L.; Chaussain, C. (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. PMID 23931057. 
  6. ↑ Fedde, Kenton (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. PMID 10620060. 
  7. ↑ Whyte, M. P. (2016). "Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment". Nature Reviews. Endocrinology 12 (4): 233–246. doi:10.1038/nrendo.2016.14. PMID 26893260. 
  8. ↑ Whyte, M. P. (2017). "Hypophosphatasia: An overview For 2017". Bone 102: 15–25. doi:10.1016/j.bone.2017.02.011. PMID 28238808. 
  9. ↑ "The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase" (in en). Nature Communications 14 (1): 4048. 2023-07-08. doi:10.1038/s41467-023-39833-3. ISSN 2041-1723. PMID 37422472. Bibcode: 2023NatCo..14.4048Y. 
  10. ↑ "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. March 2001. doi:10.1074/jbc.M009250200. PMID 11124260. 
  11. ↑ "Reaction mechanism of alkaline phosphatase based on crystal structures. Two-metal ion catalysis". Journal of Molecular Biology 218 (2): 449–464. March 1991. doi:10.1016/0022-2836(91)90724-K. PMID 2010919. 
  12. ↑ 12.0 12.1 12.2 "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. October 2002. doi:10.1038/sj.ejhg.5200857. PMID 12357339. 
  13. ↑ "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. December 2006. doi:10.1093/oxfordjournals.jbchem.a022032. PMID 17212778. 
  14. ↑ "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. July 2003. doi:10.1093/jb/mvg114. PMID 12944372. 
  15. ↑ 15.0 15.1 15.2 "Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia". Journal of Bone and Mineral Research 14 (12): 2015–2026. December 1999. doi:10.1359/jbmr.1999.14.12.2015. PMID 10620060. 

Further reading

External links



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