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Alkaline Phosphatase: An Overview

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Abstract

Alkaline phosphatase (ALP; E.C.3.I.3.1.) is an ubiquitous membrane-bound glycoprotein that catalyzes the hydrolysis of phosphate monoesters at basic pH values. Alkaline phosphatase is divided into four isozymes depending upon the site of tissue expression that are Intestinal ALP, Placental ALP, Germ cell ALP and tissue nonspecific alkaline phosphatase or liver/bone/kidney (L/B/K) ALP. The intestinal and placental ALP loci are located near the end of long arm of chromosome 2 and L/B/K ALP is located near the end of the short arm of chromosome 1. Although ALPs are present in many mammalian tissues and have been studied for the last several years still little is known about them. The bone isoenzyme may be involved in mammalian bone calcification and the intestinal isoenzyme is thought to play a role in the transport of phosphate into epithelial cells of the intestine. In this review, we tried to provide an overview about the various forms, structure and functions of alkaline phosphatase with special focus on liver/bone/kidney alkaline phosphatase.

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References

  1. McComb RB, Bowers GN, Posen S. Alkaline phosphatase. New York: Plenum Publishing Corp; 1979.

    Book  Google Scholar 

  2. Tsai LC, Hung MW, Chen YH, Su WC, Chang GG, Chang TC. Expression and regulation of alkaline phosphatases in human breast cancer MCF-7 cells. Eur J Biochem. 2000;267:1330–9.

    Article  CAS  PubMed  Google Scholar 

  3. Chang TC, Wang JK, Hung MW, Chiao CH, Tsai LC, Chang GG. Regulation of the expression of alkaline phosphatase in a human breast cancer cell line. Biochem J. 1994;303:199–205.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Whyte MP, Landt M, Ryan LM, Mulivor RA, Henthorn PS, Fedde KN, Mahuren JD, Coburn SP. Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5′-phosphate substrate accumulation in carriers of hypophosphatasia corrects during pregnancy. J Clin Invest. 1995;95:1440–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Calhau C, Martel F, Hipolito-Reis C, Azevedo I. Effect of P-glycoprotein modulators on alkaline phosphataseactivity in cultured rat hepatocytes. Cell Physiol Biochem. 2000;10:195–202.

    Article  CAS  PubMed  Google Scholar 

  6. Sadeghirishi A, Yazdanparast R. Plasma membrane homing of tissue nonspecific alkaline phosphatase under the influence of 3-hydrogenkwadaphnin, an anti-proliferative agent from Dendrostellera lessertii. Acta Biochim Pol. 2007;54:323–9.

    Google Scholar 

  7. Shigenari A, Ando A, Baba R, Vaniamoti T, Katsuoka Y, Inoko H. Characterization of alkaline phosphatase genes expressed in seminoma by cDNA cloning. Cancer Res. 1998;58:5079–82.

    CAS  PubMed  Google Scholar 

  8. Benham F, Cottell DC, Franks M, Wilson PD. Alkaline phosphatase activity in human bladder tumor cell lines. J Histochem Cytochem. 1977;25:266–74.

    Article  CAS  PubMed  Google Scholar 

  9. Mornet E, Stura E, Lia-Baldin AS, Stigbrand T, Menez A, Le Du MH. Structural evidence for a functional role of human tissue non specific alkaline phosphatase in bone mineralization. J Biol Chem. 2001;276:31171–8.

    Article  CAS  PubMed  Google Scholar 

  10. 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. Proc Natl Acad Sci. 1986;83:7182–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Sharma U, Singh SK, Pal D, Khajuria R, Mandal AK, Prasad R. Implication of BBM lipid composition and fluidity in mitigated alkaline phosphatase activity in renal cell carcinoma. Mol Cell Biochem. 2012;369:287–93.

    Article  CAS  PubMed  Google Scholar 

  12. Hoylaerts MF, Manes T, Millan JL. Mammalian alkaline phosphatases are allosteric enzymes. J Biol Chem. 1997;272:22781–7.

    Article  CAS  PubMed  Google Scholar 

  13. Sligbrand T. Present status and future trends of human alkaline phosphatases. Prog Clin Biol Res. 1984;166:3–14.

    Google Scholar 

  14. Henthorn PS, Raducha M, Fedde KN, Lefferty MA, Whyte MP. Different missense mutations at the tissue nonspecific alkaline phosphatase genes locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci. 1992;89:9924–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Millan JL, Fishman WH. Biology of human alkaline phosphatase with special reference to cancer. Crit Rev Clin Lab Sci. 1995;32:1–39.

    Article  CAS  PubMed  Google Scholar 

  16. Muller H, Yamazaki M, Michigami T, Kageyama T, Chonau E, Schneider P, Ozono K. Asp361Val mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme. J Clinical Endocrinol Metabolism. 2000;85:743–7.

    Article  CAS  Google Scholar 

  17. Mulivor RA, Plotkin LI, Harris H. Developmental change in human intestinal alkaline phosphatase. Ann Hum Genet. 1978;42:1–13.

    Article  CAS  PubMed  Google Scholar 

  18. McKenna MJ, Hamilton TA, Sussman HH. Comparison of human alkaline phosphatase isoenzymes. structural evidence for three protein classes. Biochem J. 1979;181:67–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Harris H. The harvey lectures: series 76. New York: Academic; 1986. p. 95–123.

    Google Scholar 

  20. Raimondi E, Talarico D, Moro L, et al. Regional mapping of the human placental alkaline phosphatase gene (ALP) to 2q37 by in situ hybridization. Cyrogenet Cell Genet. 1988;47:98–9.

    Article  CAS  Google Scholar 

  21. Henthom PS, Raducha M, Hadesch T, et al. Sequence and characterization of the human intestinal alkaline phosphatase gene. J Biol Chem. 1988;263:12011–9.

    Google Scholar 

  22. Vergote IB, Abeler VM, Bormer OP, et al. CA125 and placental alkaline phosphatase as serum tumor markers in epithelial ovarian carcinoma. Tumor Biol. 1992;13:168–74.

    Article  CAS  Google Scholar 

  23. Fishman WH, Inglis NR, Green S, et al. Immunology and biochemistry of regan isoenzyme of alkaline phosphatase in human cancer. Nature. 1968;219:697–9.

    Article  CAS  PubMed  Google Scholar 

  24. Griffin CA, Smith M, Henthorn PS, et al. Human placental and intestinal alkaline phosphatase genes map to 2q34–q37. Am J Hum Genet. 1987;41:1025–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Komoda T, Sakagishi Y. The function of the carbohydrate moiety and alteration of carbohydrate composition in human alkaline phosphatase isoenzymes. Biochim Biophys Acta. 1978;523:395–406.

    Article  CAS  PubMed  Google Scholar 

  26. Higashino K, Muratani K, Hade T, et al. Gene structure of alkaline phosphatases: purification and some properties of the fast migrating alkaline phosphatase in FL-amnion cells (the Kasahara isoenzyme) and its cDNA cloning. Clin Chim Acta. 1989;186:151–64.

    Article  Google Scholar 

  27. Millan JL. Molecular cloning and sequence analysis of human placental alkaline phosphatase. J Biol Chem. 1986;261:3112–5.

    CAS  PubMed  Google Scholar 

  28. Millan JL, Manes R. Seminoma-derived nagao isozyme is encoded by a germ cell alkaline phosphatase gene. Proc Natl Acad Sci. 1988;85:3024–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Hofmann MC, Jeltsch W, Brecher J, Walt H. Alkaline phosphatase isozymes in human testicular germ cell tumors, precancerous stage, and three related cell lines. Cancer Res. 1989;49:4696–700.

    CAS  PubMed  Google Scholar 

  30. Povinelli CM, Knoll BJ. Trace expression of the germ-cell alkaline phosphatase gene in human placenta. Placenta. 1991;12(663):8.

    Google Scholar 

  31. Fishman WH. Clinical and biological significance of an isoenzyme tumor marker-PLAP. Clin Biochem. 1987;20:387–92.

    Article  CAS  PubMed  Google Scholar 

  32. Smith M, Weiss MJ, Griffin CA, et al. Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1 p36.1–p34. Genomics. 1988;2:139–43.

    Article  CAS  PubMed  Google Scholar 

  33. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77:4–12.

    Article  CAS  PubMed  Google Scholar 

  34. Fishman WH. Alkaline phosphatase isozymes: recent progress. Clin Biochem. 1990;23:99–104.

    Article  CAS  PubMed  Google Scholar 

  35. Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H. Structure of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem. 1988;263:12002–10.

    CAS  PubMed  Google Scholar 

  36. Du MHL, Milla JL. Structural evidence of functional divergence in human alkaline phosphatases. J Biol Chem. 2002;277:49808–14.

    Article  PubMed  Google Scholar 

  37. Moss DW. Perspectives in alkaline phosphatase research. Clin Chem. 1992;38:2486–92.

    CAS  PubMed  Google Scholar 

  38. Kiledjian M, Kadesch T. Post-transcriptional regulation of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem. 1991;266:4207–13.

    CAS  PubMed  Google Scholar 

  39. Harris H. The human alkaline phosphatases: what we know and what we don’t know. Clin Chim Acta. 1990;186:133–50.

    Article  CAS  PubMed  Google Scholar 

  40. Bradshaw RA, Cancedda F, Ericsson LH, Neumann PA, Piccoli SP, Schlesinger MJ, Shriefer K, Walsh KA. Amino acid sequence of Escherichia coli alkaline phosphatase. Proc Natl Acad Sci. 1981;78:3473–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Henthorn PS, Raducha M, Edwards YN, Weiss MJ, Slaughter C, Lafferty MA, Harris H. Nucleotide and amino acid sequences of human intestinal alkaline phosphatase: close homology to placental alkaline phosphatase. Proc Natl Acad Sci. 1984;84:1234–8.

    Article  Google Scholar 

  42. Weiss MJ, Cole DEC, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a form of lethal hypophosphatasia. Proc Natl Acad Sci. 1988;85:7666–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Kam W, Clauser E, Kim YS, Kan YW, Rutter WJ. Cloning, sequencing, and chromosomal localization of human term placental alkaline phosphatase cDNA. Proc Natl Acad Sci. 1985;82:8715–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Sowadski JM, Handschumacher MD, Murthy HMK, Foster BA, Wyckoff HW. Refined structure of alkaline phosphatase from Escherichia coli at 2.8 A resolution. J Mol Biol. 1985;186:417–33.

    Article  CAS  PubMed  Google Scholar 

  45. Llinas P, Masella M, Stigbrand T, Menez A, Stura EA, Le Du MH. Structural studies of human alkaline phosphatase in complex with strontium: implication for its secondary effect in bones. Protein Sci. 2006;15:1691–700.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Yoko I, Keiichi K, Masahiro I, Yoshihiro A, Shoji K, Kimimitsu O. Tissue-nonspecific alkaline phosphatase with an Asp289 → Val mutation fails to reach the cell surface and undergoes proteosome-mediated degradation. J Biochem. 2003;134:63–70.

    Article  Google Scholar 

  47. Suzuki U, Yoshimura K, Takashi M. Uber ein enzyme ―phytase‖ das anhydro-oxy-methylen-diphosphorsaure spaltet. Bull Coll Agri Tokyo Imp Univ. 1907;7:503–12.

    Google Scholar 

  48. Wuthier RE, Register T. Role of alkaline phosphatase, a polyfunctional enzyme, in mineralizing tissues. In: Butler WT, editor. Chemistry and biology of mineralized tissues. Birmingham: EBSCO Media; 1985. p. 113–24.

    Google Scholar 

  49. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190–200.

    Article  CAS  PubMed  Google Scholar 

  50. Zhu T, Gan YH, Liu H. Functional evaluation of mutations in the tissue-nonspecific alkaline phosphatase gene. Chin J Dent Res. 2012;15:99–104.

    CAS  PubMed  Google Scholar 

  51. Moss DW. Aspects of the relationship between liver, kidney and bone alkaline phosphatase. In: Stigbrand T, Fishman WH, editors. Human alkaline phosphatases. New York: Alan R Liss; 1984. p. 79–86.

    Google Scholar 

  52. Epstein E, Kiechle FL, Artiss JD, Zak B. The clinical use of alkaline phosphatase enzymes. Clin Lab Med. 1986;6:491–505.

    CAS  PubMed  Google Scholar 

  53. Rodan GA, Rodan SB. In: Peck WA, editor. Advances in bone and mineral research annual II. Amsterdam: Excerpta Medica; 1984. p. 244–85.

    Google Scholar 

  54. Preussner HT. Detecting coeliac disease in your patients. Am Fam Physician. 1998;57:1023–34.

    Google Scholar 

  55. Lange PH, Millan JL, Stigbrand T, Vessella RL, Ruoslahti E, Fishman WH. Placental alkaline phosphatase as a tumor marker for seminoma. Cancer Res. 1982;42:3244–7.

    CAS  PubMed  Google Scholar 

  56. Schiele F, Vincent-Viry M, Fournier B, Starck M, Siest G. Biological effects of eleven combined oral contraceptives on serum triglycerides, gamma-glutamyltransferase, alkaline phosphatase, bilirubin and other biochemical variables. Clin Chem Lab Med. 1998;36:871–8.

    Article  CAS  PubMed  Google Scholar 

  57. Buchet R, Millán JL, Magne D. Multisystemic functions of alkaline phosphatases. Methods Mol Biol. 2013;1053:27–51.

    Article  PubMed  Google Scholar 

  58. Mueller HD, Stinson RA, Mohyuddin F, Milne JK. Isoenzymes of alkaline phosphatase in infantile hypophosphatasia. J Lab Clin Med. 1983;102:24–30.

    CAS  PubMed  Google Scholar 

  59. Sultana S, Al-Shawafi HA, Makita S, Sohda M, Amizuka N, Takagi R, Oda K. An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. Mol Genet Metab. 2013;109:282–8.

    Article  CAS  PubMed  Google Scholar 

  60. Chang KC, Lin PH, Su YN, Peng SS, Lee NC, Chou HC, Chen CY, Hsieh WS, Tsao PN. Novel heterozygous tissue-nonspecific alkaline phosphatase (TNAP) gene mutations causing lethal perinatal hypophosphatasia. J Bone Miner Metab. 2012;30:109–13.

    Article  PubMed  Google Scholar 

  61. Usoro NI, Omabbe MC, Usoro CAO, Nsonwu A. Calcium, inorganic phosphates, alkaline and acid phosphatase activities in breast cancer patients in Calabar, Nigeria. African Health Sci. 2010;10:9–13.

    Google Scholar 

  62. Prasad R, Lambe S, Kaler P, Pathania S, Kumar S, Attari S, Singh SK. Ectopic expression of alkaline phosphatase in proximal tubular brush border membrane of human renal cell carcinoma. Biochim et Biophy acta. 2005;1741:240–5.

    Article  CAS  Google Scholar 

  63. Niedermayer I, Feiden W, Henn W, Steilen-Gimbel H, Steudel WI, Zang KD. Loss of alkaline phosphatase activity in meningiomas: a rapid histochemical technique indicating progression-associated deletion of a putative tumor suppressor gene on the distal part of the short arm of chromosome 1. J Neuropathol Exp Neurol. 1997;56:879–86.

    Article  CAS  PubMed  Google Scholar 

  64. Kim JM, Kwon CH, Joh JW, Park JB, Ko JS, Lee JH, Kim SJ, Park CK. The effect of alkaline phosphatase and intrahepatic metastases in large hepatocellular carcinoma. World J Surg Oncol. 2013;11:40.

    Article  PubMed Central  PubMed  Google Scholar 

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Correspondence to Rajendra Prasad.

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Sharma, U., Pal, D. & Prasad, R. Alkaline Phosphatase: An Overview. Ind J Clin Biochem 29, 269–278 (2014). https://doi.org/10.1007/s12291-013-0408-y

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