Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.[5][6]
Function[edit]
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).[7][8][9][10] 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.[11][12]
Structure[edit]
Tissue Non-Specific Alkaline Phosphatase (TNAP), encoded by the ALPL gene, exhibits an intriguing octameric structure as revealed by X-ray crystallography.[13] This distinct arrangement consists of four individual dimeric TNAP units. Structural studies on homologs of TNAP, namely human (ALPP)[14] and Escherichia coli (ecPhoA),[15] 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[edit]
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[16] depending upon which amino acid[17][18] 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).[19] There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait,[16] the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth.[19] ALPL gene mutation leads to insufficient TNSALP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate[19] 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.[16]
References[edit]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000162551 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028766 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ Swallow DM, Povey S, Parkar M, Andrews PW, Harris H, Pym B, Goodfellow P (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.
- ^ McKee MD, Nakano Y, Masica DL, Gray JJ, Lemire I, Heft R, Whyte MP, Crine P, Millán JL (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.
- ^ Millán JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP (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.
- ^ McKee MD, Hoac B, Addison WN, Barros NM, Millán JL, 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. PMC 3766584. PMID 23931057.
- ^ Fedde K (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.
- ^ Whyte MP (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.
- ^ Whyte MP (2017). "Hypophosphatasia: An overview For 2017". Bone. 102: 15–25. doi:10.1016/j.bone.2017.02.011. PMID 28238808.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b c 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.
- ^ Nasu M, Ito M, Ishida Y, Numa N, Komaru K, Nomura S, Oda K (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.
- ^ 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.
- ^ a b c 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[edit]
- Mornet E (2000). "Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene". Human Mutation. 15 (4): 309–315. doi:10.1002/(SICI)1098-1004(200004)15:4<309::AID-HUMU2>3.0.CO;2-C. PMID 10737975. S2CID 45944100.
- Khandwala HM, Mumm S, Whyte MP (2007). "Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood". Endocrine Practice. 12 (6): 676–681. doi:10.4158/ep.12.6.676. PMID 17229666.
- Nye KE, Riley GA, Pinching AJ (July 1992). "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. doi:10.1111/j.1365-2249.1992.tb06883.x. PMC 1554388. PMID 1321014.
- Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP (October 1992). "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. Bibcode:1992PNAS...89.9924H. doi:10.1073/pnas.89.20.9924. PMC 50246. PMID 1409720.
- Nishihara Y, Hayashi Y, Adachi T, Koyama I, Stigbrand T, Hirano K (December 1992). "Chemical nature of intestinal-type alkaline phosphatase in human kidney". Clinical Chemistry. 38 (12): 2539–2542. doi:10.1093/clinchem/38.12.2539. PMID 1458595.
- Fedde KN, Whyte MP (November 1990). "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. PMC 1683690. PMID 2220817.
- Kishi F, Matsuura S, Kajii T (March 1989). "Nucleotide sequence of the human liver-type alkaline phosphatase cDNA". Nucleic Acids Research. 17 (5): 2129. doi:10.1093/nar/17.5.2129. PMC 317555. PMID 2928120.
- Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H (August 1988). "Structure of the human liver/bone/kidney alkaline phosphatase gene". The Journal of Biological Chemistry. 263 (24): 12002–12010. doi:10.1016/S0021-9258(18)37885-2. PMID 3165380.
- Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H (October 1988). "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. Bibcode:1988PNAS...85.7666W. doi:10.1073/pnas.85.20.7666. PMC 282253. PMID 3174660.
- Smith M, Weiss MJ, Griffin CA, Murray JC, Buetow KH, Emanuel BS, et al. (February 1988). "Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1p36.1-p34". Genomics. 2 (2): 139–143. doi:10.1016/0888-7543(88)90095-X. PMID 3410475. S2CID 28142633.
- Garattini E, Hua JC, Pan YC, Udenfriend S (March 1986). "Human liver alkaline phosphatase, purification and partial sequencing: homology with the placental isozyme". Archives of Biochemistry and Biophysics. 245 (2): 331–337. doi:10.1016/0003-9861(86)90223-7. PMID 3954357.
- Goldstein DJ, Blasco L, Harris H (July 1980). "Placental alkaline phosphatase in nonmalignant human cervix". Proceedings of the National Academy of Sciences of the United States of America. 77 (7): 4226–4228. Bibcode:1980PNAS...77.4226G. doi:10.1073/pnas.77.7.4226. PMC 349804. PMID 6933471.
- Sato N, Takahashi Y, Asano S (February 1994). "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. doi:10.1182/blood.V83.4.1093.1093. PMID 7509208.
- Orimo H, Hayashi Z, Watanabe A, Hirayama T, Hirayama T, Shimada T (September 1994). "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. doi:10.1093/hmg/3.9.1683. PMID 7833929.
- Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN (July 1993). "A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites". Genomics. 17 (1): 215–217. doi:10.1006/geno.1993.1305. PMID 8406453.
- Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, Cai G, et al. (December 1996). "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. doi:10.1210/jcem.81.12.8954059. PMID 8954059.
- Orimo H, Goseki-Sone M, Sato S, Shimada T (June 1997). "Detection of deletion 1154-1156 hypophosphatasia mutation using TNSALP exon amplification". Genomics. 42 (2): 364–366. doi:10.1006/geno.1997.4733. PMID 9192863.
- Sugimoto N, Iwamoto S, Hoshino Y, Kajii E (1998). "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. doi:10.1007/s100380050061. PMID 9747027.
External links[edit]
- GeneReviews/NCBI/NIH/UW entry on Hypophosphatasia
- Human ALPL genome location and ALPL gene details page in the UCSC Genome Browser.