Properties of Tissue-Nonspecific Alkaline Phosphatase from Mammalian Testes

The enzyme systems of living organisms catalyse biochemical reactions and are an important component of the functioning of organs and systems. Alkaline phosphatase is localised on the plasma membranes of cells and catalyses the hydrolysis of the phosphoester bond. This enzyme is found in liver, bone, kidney, intestine, placenta and many other organs and tissues. Levels of alkaline phosphatase activity can be altered in various diseases. Despite the universality of the mechanism of action, the function of alkaline phosphatase is poorly understood. Characteristics of alkaline phosphatase isoenzymes, both tissue-specific and tissue-specific: intestinal, germinal, placental. The analysis of literature data on the study of tissue-specific alkaline phosphatase function in bone calcification, in the accumulation of triglycerides by adipose tissue cells, in embryonic development and in spermatogenesis is performed. This review presents an analysis of data on the localisation of alkaline phosphatase in mammalian testes. Alkaline phosphatase was detected in the peritubular cells of the seminiferous tubules and in spermatogonia. Weak reactivity to alkaline phosphatase was observed in Sertoli cells. The enzyme is species-specific: it has been detected in the testes of rats, mice, dogs, guinea pigs, and human testes. Hamsters, rabbits, and bats do not express alkaline phosphatase. The molecular structure of alkaline phosphatase and its properties in relation to standard inhibitors have been characterised. However, the effect of the enzyme on the differentiation of primary germ cells and on the maturation of spermatogenesis cells in mammalian testes has not been studied. Further studies are needed to determine the role of alkaline phosphatase in the physiology of cells and tissues of the reproductive system, including germ cell meiosis.

1. Ali AT, Penny CB, Paiker JE, van Niekerk C, Smit A, Ferris WF, et al Alkaline phosphatase is involved in the control of adipogenesis in the murine preadipocyte cell line, 3T3-L1. Clin Chim Acta. 2005 Apr;354(1-2):101-9. doi: 10.1016/j.cccn.2004.11.026.

2. Bisswanger. Prakticheskaya ehnzimologiya. Germany: Wiley-VCH Verlag & Co. KGaA; 2011.360. https://doi.org/10.1002/9783527659227.

3. Bodansky O, Schwartz MK. Comparative effects of l-histidine on the activities of 5'- nucleotidase and alkaline phosphatase. The Journal of biological chemistry. 1963;238:3420-3427.

4. Borgers M. The cytochemical application of new potent inhibitors of alkaline phosphatases. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 1973;21(9):812-824. https://doi.org/10.1177/21.9.812.

5. Borosky GL. Catalytic activity of human placental alkaline phosphatase (PLAP): insights from a computational study. The journal of physical chemistry B. 2014;118(49):14302-14313. https://doi.org/10.1021/jp511221c.

6. Chang CH, Angellis D, Fishman WH. Presence of the rare D-variant heat-stable, placental-type alkaline phosphatase in normal human testis. Cancer research. 1980;40(5):1506-1510.

7. Chapin RE, Phelps JL, Miller BE, Gray TJ. Alkaline phosphatase histochemistry discriminates peritubular cells in primary rat testicular cell culture. Journal of andrology. 1987;8(3):155-61. https://doi.org/10.1002/j.1939-4640.1987.tb02427.x.

8. Choi H, Kim TH, Yun CY, Kim JW, Cho ES. Testicular acid phosphatase induces odontoblast differentiation and mineralization. Cell and tissue research. 2016;364(1):95-103. https://doi.org/10.1007/s00441-015-2310-9.

9. Fernley HN, Walker PG. Inhibition of alkaline phosphatase by L-phenylalanine. The Biochemical journal. 1970;116(3):543-544. https://doi.org/10.1042/bj1160543.

10. Fishman W, Sie HG. L-homoarginine; an inhibitor of serum "bone and liver" alkaline phosphatase. Clinica chimica acta; international journal of clinical chemistry. 1970;29(2):339-341. https://doi.org/10.1016/0009-8981(70)90057-4.

11. Garimella R, Bi X, Anderson HC, Camacho NP. Nature of phosphate substrate as a major determinant of mineral type formed in matrix vesiclemediated in vitro mineralization: An FTIR imaging study. Bone. 2006;38(6):811-817. https://doi.org/10.1016/j.bone.2005.11.027.

12. Harrison G, Shapiro IM, Golub EE. The phosphatidylinositol-glycolipid anchor on alkaline phosphatase facilitates mineralization initiation in vitro. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1995;10(4):568-573. https://doi.org/10.1002/jbmr.5650100409.

13. Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. Science (New York, NY). 2000;289(5477):265-270. https://doi.org/10.1126/science.289.5477.265.

14. Hoylaerts MF, Manes T, Millán JL. Molecular mechanism of uncompetitive inhibition of human placental and germ-cell alkaline phosphatase. Biochem J. 1992 Aug 15;286 ( Pt 1)(Pt 1):23-30. doi: 10.1042/bj2860023.

15. Kornblatt MJ, Klugerman A, Nagy F. Characterization and localization of alkaline phosphatase activity in rat testes. Biology of reproduction. 1983;29(1):157-164. https://doi.org/10.1095/biolreprod29.1.157.

16. Kurimoto K, Yabuta Y, Ohinata Y, Shigeta M, Yamanaka K, Saitou M. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes & development. 2008;22(12):1617-1635. https://doi.org/10.1101/gad.1649908.

17. Kutzler MA, Solter PF, Hoffman WE, Volkmann DH. Characterization and localization of alkaline phosphatase in canine seminal plasma and gonadal tissues. Theriogenology. 2003;60(2):299- 306. https://doi.org/10.1016/s0093-691x(02)01366-3.

18. Lepire ML, Ziomek CA. Preimplantation mouse embryos express a heat-stable alkaline phosphatase. Biology of reproduction. 1989;41(3):464- 473. https://doi.org/10.1095/biolreprod41.3.464.

19. Lewin LM, Golan R, Soffer Y, Kaufman S, Yulzary Y, Zaidman J. Alkaline phosphatase in human semen: an investigation using enzyme inhibitors and gel electrophoresis. European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies. 1993;31(12):811-814. https://doi.org/10.1515/cclm.1993.31.12.811.

20. Lin CW, Fishman WH. L-Homoarginine. An organ-specific, uncompetitive inhibitor of human liver and bone alkaline phosphohydrolases. The Journal of biological chemistry. 1972;247(10):3082-3087.

21. Lin CW, Sie HG, Fishman WH. L-tryptophan. A non-allosteric organ-specific uncompetitive inhibitor of human placental alkaline phosphatase. The Biochemical journal. 1971;124(3):509-516. https://doi.org/10.1042/bj1240509.

22. MacGregor GR, Zambrowicz BP, Soriano P. Tissue non-specific alkaline phosphatase is expressed in both embryonic and extraembryonic lineages during mouse embryogenesis but is not required for migration of primordial germ cells. Development (Cambridge, England). 1995;121(5):1487-1496. https://doi.org/10.1242/dev.121.5.1487.

23. McLaughlin PJ, Lewis-Jones I, Hutchinson GE, Johnson PM. Placental-type alkaline phosphatase in human seminal plasma from fertile and infertile men. Fertility and sterility. 1986;46(5):934-937.

24. Merchant-Larios H, Mendlovic F, Alvarez-Buylla A. Characterization of alkaline phosphatase from primordial germ cells and ontogenesis of this enzyme in the mouse. Differentiation; research in biological diversity. 1985;29(2):145-151. https://doi.org/10.1111/j.1432-0436.1985.tb00308.x.

25. Millán JL. Alkaline Phosphatases : Structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic signalling. 2006;2(2):335-341. https://doi.org/10.1007/s11302-005-5435-6.

26. Mulnard J, Huygens R. Ultrastructural localization of non-specific alkaline phosphatase during cleavage and blastocyst formation in the mouse. Journal of embryology and experimental morphology. 1978;44:121-131.

27. Narisawa S, Harmey D, Magnusson P, Millán JL. Conserved epitopes in human and mouse tissuenonspecific alkaline phosphatase. Second report of the ISOBM TD-9 workshop. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2005;26(3):113-120. https://doi.org/10.1159/000086482.

28. Narisawa S, Hofmann MC, Ziomek CA, Millán JL. Embryonic alkaline phosphatase is expressed at M-phase in the spermatogenic lineage of the mouse. Development (Cambridge, England). 1992;116(1):159-165. https://doi.org/10.1242/dev.116.1.159.

29. O'Brien PJ, Herschlag D. Alkaline phosphatase revisited: hydrolysis of alkyl phosphates. Biochemistry. 2002 Mar 5;41(9):3207-25. doi: 10.1021/bi012166y.

30. Roelofs H, Manes T, Janszen T, Millán JL, Oosterhuis JW, Looijenga LH. Heterogeneity in alkaline phosphatase isozyme expression in human testicular germ cell tumours: An enzyme- /immunohistochemical and molecular analysis. J Pathol. 1999 Oct;189(2):236-44. doi: 10.1002/(SICI)1096-9896(199910)189:23.0.CO;2-J.

31. Saini D, Kala M, Jain V, Sinha S. Targeting the active site of the placental isozyme of alkaline phosphatase by phage-displayed scFv antibodies selected by a specific uncompetitive inhibitor. BMC biotechnology. 2005;5:33. https://doi.org/10.1186/1472-6750-5-33.

32. Saitou M, Barton SC, Surani MA. A molecular programme for the specification of germ cell fate in mice. Nature. 2002;418(6895):293-300. https://doi.org/10.1038/nature00927.

33. Sebastián-Serrano Á, de Diego-García L, Martínez-Frailes C, Ávila J, Zimmermann H, Millán JL, et al. Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease. Comput Struct Biotechnol J. 2014 Dec 15;13:95-100. doi: 10.1016/j.csbj.2014.12.004.

34. Soma K, Izumi M, Yamamoto Y, Miyazaki S, Watanabe K. In Vitro and In Vivo Pharmacological Profiles of DS-1211, a Novel Potent, Selective, and Orally Bioavailable Tissue-Nonspecific Alkaline Phosphatase Inhibitor. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022;37(10):2033-43. https://doi.org/10.1002/jbmr.4680.

35. Wang P, Suo LJ, Shang H, Li Y, Li GX, Li QW, et al. Differentiation of spermatogonial stem cell-like cells from murine testicular tissue into haploid male germ cells in vitro. Cytotechnology. 2014 May;66(3):365-72. doi: 10.1007/s10616-013-9584-0.

36. Wang W, Xu J, Du B, Kirsch T. Role of the progressive ankylosis gene (ank) in cartilage mineralization. Molecular and cellular biology. 2005;25(1):312-323.

37. Yamashita T, Sawanobori-isobe E, Mori M. Stabilization of human serum alkaline phosphatase to histidine-induced heat inactivation by tryptic digestion. Journal of biochemistry. 1976;80(1):129- 134. doi: 10.1093/oxfordjournals.jbchem.a131244

38. Zaher DM, El-Gamal MI, Omar HA, Aljareh SN, Al-Shamma SA, Ali AJ, et al. Recent advances with alkaline phosphatase isoenzymes and their inhibitors. Arch Pharm (Weinheim). 2020 May;353(5):e2000011. doi: 10.1002/ardp.202000011.

39. Zhang H, Yang L, Ding W, Ma Y. The pHdependent activation mechanism of Ser102 in Escherichia coli alkaline phosphatase: a theoretical study. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2018;23(2):277-284. https://doi.org/10.1007/s00775-017-1529-1