ALPL explained

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, 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 TNSALP 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.

References

Further reading

• Mornet E . Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene . Human Mutation . 15 . 4 . 309–315 . 2000 . 10737975 . 10.1002/(SICI)1098-1004(200004)15:4<309::AID-HUMU2>3.0.CO;2-C . 45944100 . free .
• Khandwala HM, Mumm S, Whyte MP . Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood . Endocrine Practice . 12 . 6 . 676–681 . 2007 . 17229666 . 10.4158/ep.12.6.676 .
• Nye KE, Riley GA, Pinching AJ . The defect seen in the phosphatidylinositol hydrolysis pathway in HIV-infected lymphocytes and lymphoblastoid cells is due to inhibition of the inositol 1,4,5-trisphosphate 1,3,4,5-tetrakisphosphate 5-phosphomonoesterase . Clinical and Experimental Immunology . 89 . 1 . 89–93 . July 1992 . 1321014 . 1554388 . 10.1111/j.1365-2249.1992.tb06883.x .
• Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP . Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia . Proceedings of the National Academy of Sciences of the United States of America . 89 . 20 . 9924–9928 . October 1992 . 1409720 . 50246 . 10.1073/pnas.89.20.9924 . free . 1992PNAS...89.9924H .
• Nishihara Y, Hayashi Y, Adachi T, Koyama I, Stigbrand T, Hirano K . Chemical nature of intestinal-type alkaline phosphatase in human kidney . Clinical Chemistry . 38 . 12 . 2539–2542 . December 1992 . 1458595 . 10.1093/clinchem/38.12.2539 . free .
• Fedde KN, Whyte MP . Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5'-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study . American Journal of Human Genetics . 47 . 5 . 767–775 . November 1990 . 2220817 . 1683690 .
• Kishi F, Matsuura S, Kajii T . Nucleotide sequence of the human liver-type alkaline phosphatase cDNA . Nucleic Acids Research . 17 . 5 . 2129 . March 1989 . 2928120 . 317555 . 10.1093/nar/17.5.2129 .
• Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H . Structure of the human liver/bone/kidney alkaline phosphatase gene . The Journal of Biological Chemistry . 263 . 24 . 12002–12010 . August 1988 . 3165380 . 10.1016/S0021-9258(18)37885-2 . free .
• Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H . A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia . Proceedings of the National Academy of Sciences of the United States of America . 85 . 20 . 7666–7669 . October 1988 . 3174660 . 282253 . 10.1073/pnas.85.20.7666 . free . 1988PNAS...85.7666W .
• Smith M, Weiss MJ, Griffin CA, Murray JC, Buetow KH, Emanuel BS, Henthorn PS, Harris H . 6 . Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1p36.1-p34 . Genomics . 2 . 2 . 139–143 . February 1988 . 3410475 . 10.1016/0888-7543(88)90095-X . 28142633 .
• Garattini E, Hua JC, Pan YC, Udenfriend S . Human liver alkaline phosphatase, purification and partial sequencing: homology with the placental isozyme . Archives of Biochemistry and Biophysics . 245 . 2 . 331–337 . March 1986 . 3954357 . 10.1016/0003-9861(86)90223-7 .
• Goldstein DJ, Blasco L, Harris H . Placental alkaline phosphatase in nonmalignant human cervix . Proceedings of the National Academy of Sciences of the United States of America . 77 . 7 . 4226–4228 . July 1980 . 6933471 . 349804 . 10.1073/pnas.77.7.4226 . free . 1980PNAS...77.4226G .
• Sato N, Takahashi Y, Asano S . Preferential usage of the bone-type leader sequence for the transcripts of liver/bone/kidney-type alkaline phosphatase gene in neutrophilic granulocytes . Blood . 83 . 4 . 1093–1101 . February 1994 . 7509208 . 10.1182/blood.V83.4.1093.1093 . free .
• Orimo H, Hayashi Z, Watanabe A, Hirayama T, Hirayama T, Shimada T . Novel missense and frameshift mutations in the tissue-nonspecific alkaline phosphatase gene in a Japanese patient with hypophosphatasia . Human Molecular Genetics . 3 . 9 . 1683–1684 . September 1994 . 7833929 . 10.1093/hmg/3.9.1683 .
• Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN . A homoallelic Gly317→Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites . Genomics . 17 . 1 . 215–217 . July 1993 . 8406453 . 10.1006/geno.1993.1305 .
• Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, Cai G, Satomura K, Yasui N, Okada S, Nakayama M . 6 . Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia . The Journal of Clinical Endocrinology and Metabolism . 81 . 12 . 4458–4461 . December 1996 . 8954059 . 10.1210/jcem.81.12.8954059 . free .
• Orimo H, Goseki-Sone M, Sato S, Shimada T . Detection of deletion 1154-1156 hypophosphatasia mutation using TNSALP exon amplification . Genomics . 42 . 2 . 364–366 . June 1997 . 9192863 . 10.1006/geno.1997.4733 .
• Sugimoto N, Iwamoto S, Hoshino Y, Kajii E . A novel missense mutation of the tissue-nonspecific alkaline phosphatase gene detected in a patient with hypophosphatasia . Journal of Human Genetics . 43 . 3 . 160–164 . 1998 . 9747027 . 10.1007/s100380050061 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Hypophosphatasia

Notes and References

1. Weiss MJ, Henthorn PS, Lafferty MA, Slaughter C, Raducha M, Harris H . 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 . 3532105 . 386679 . 10.1073/pnas.83.19.7182 . free . 1986PNAS...83.7182W .
2. Swallow DM, Povey S, Parkar M, Andrews PW, Harris H, Pym B, Goodfellow P . 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 . 3446011 . 10.1111/j.1469-1809.1986.tb01043.x . 20363222 .
3. Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia . 2011 . 21212313 . McKee . M. D. . Nakano . Y. . Masica . D. L. . Gray . J. J. . Lemire . I. . Heft . R. . Whyte . M. P. . Crine . P. . Millán . J. L. . Journal of Dental Research . 90 . 4 . 470–476 . 10.1177/0022034510393517 . 3144124 .
4. Enzyme replacement therapy for murine hypophosphatasia . 2008 . 18086009 . Millán . J. L. . Narisawa . S. . Lemire . I. . Loisel . T. P. . Boileau . G. . Leonard . P. . Gramatikova . S. . Terkeltaub . R. . Camacho . N. P. . McKee . M. D. . Crine . P. . Whyte . M. P. . Journal of Bone and Mineral Research . 23 . 6 . 777–787 . 10.1359/jbmr.071213 . 2652241 .
5. Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia . 2013 . 23931057 . McKee . M. D. . Hoac . B. . Addison . W. N. . Barros . N. M. . Millán . J. L. . Chaussain . C. . Periodontology 2000 . 63 . 1 . 102–122 . 10.1111/prd.12029 . 3766584 .
6. Fedde . Kenton . Alkaline Phosphatase Knock-Out Mice Recapitulate the Metabolic and Skeletal Defects of Infantile Hypophosphatasia . Journal of Bone and Mineral Research . 1999 . 14 . 12 . 2015–2026 . 10.1359/jbmr.1999.14.12.2015 . 10620060. 3049802 .
7. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment . 2016 . 26893260 . Whyte . M. P. . Nature Reviews. Endocrinology . 12 . 4 . 233–246 . 10.1038/nrendo.2016.14 . 20805434 .
8. Hypophosphatasia: An overview For 2017 . 2017 . 28238808 . Whyte . M. P. . Bone . 102 . 15–25 . 10.1016/j.bone.2017.02.011 .
9. 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 . 6 . 2023-07-08 . The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase . Nature Communications . en . 14 . 1 . 4048 . 10.1038/s41467-023-39833-3 . 37422472 . 2041-1723. 10329691 . 2023NatCo..14.4048Y .
10. Le Du MH, Stigbrand T, Taussig MJ, Menez A, Stura EA . 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 . 11124260 . 10.1074/jbc.M009250200 . free .
11. Kim EE, Wyckoff HW . Reaction mechanism of alkaline phosphatase based on crystal structures. Two-metal ion catalysis . Journal of Molecular Biology . 218 . 2 . 449–464 . March 1991 . 2010919 . 10.1016/0022-2836(91)90724-K .
12. Hérasse M, Spentchian M, Taillandier A, Mornet E . 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 . 12357339 . 10.1038/sj.ejhg.5200857 . free .
13. Nasu M, Ito M, Ishida Y, Numa N, Komaru K, Nomura S, Oda K . 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 . 17212778 . 10.1093/oxfordjournals.jbchem.a022032 .
14. Ishida Y, Komaru K, Ito M, Amaya Y, Kohno S, Oda K . 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 . 12944372 . 10.1093/jb/mvg114 .
15. Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millán JL, MacGregor GR, Whyte MP . 6 . 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 . 10620060 . 3049802 . 10.1359/jbmr.1999.14.12.2015 .