Skip to main content
SpringerLink
Log in

Mechanisms of cell death induction by L-amino acid oxidase, a major component of ophidian venom

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

L-amino acid oxidase (LAAO) from the Malayan pit viper induces both necrosis and apoptosis in Jurkat cells. Cell death by necrosis is attributed to H2O2 produced by oxidation of α-amino acids. In the presence of catalase that effectively scavenges H2O2, a switch to apoptosis is observed. The major factors contributing to apoptosis are proposed to be: (i) generation of toxic intermediates from fetal calf serum (ii) binding and internalization of LAAO. The latter process appears to be mediated by the glycan moiety of the enzyme as desialylation reduces cytotoxicity. D-amino acid oxidase (DAAO), which catalyzes the same reaction as LAAO but lacks glycosylation, triggers necrosis as a consequence of H2O2 production but not apoptosis in the presence of catalase. Thus induction of cell death by LAAO appears to involve both the generation of H2O2 and the molecular interaction of the glycan moiety of the enzyme with structures at the cell surface.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AIP:

Apoptosis-inducing protein

DAAO:

D-Amino acid oxidase

LAAO:

L-Amino acid oxidase

zVAD-fmk:

benzyloxycarbonyl-Val-Ala-Asp-CH2OC (O)-2,6 dichloro benzene, fluoro methyl ketone

DEVD-AFC:

Asp-Glu-Val-Asp 7-amino-4-trifluoromethyl coumarin

FCS:

Fetal calf serum

Lpt-medium:

LAAO pretreated-medium

References

  1. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92:7162–7166

    Article  PubMed  CAS  Google Scholar 

  2. Dypbukt JM, Ankarcrona M, Burkitt M, Sjoholm A, Strom K, Orrenius S, Nicotera P (1994) Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINm5F cells. The role of intracellular polyamines. J Biol Chem 269:30553–30560

    PubMed  CAS  Google Scholar 

  3. Nicotera P, Leist M, Ferrando-May E (1998) Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicol Lett 102–103:139–142

    Article  PubMed  Google Scholar 

  4. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15:961–973

    Article  PubMed  CAS  Google Scholar 

  5. Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486

    Article  PubMed  CAS  Google Scholar 

  6. Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57:1835–1840

    PubMed  CAS  Google Scholar 

  7. Zamaraeva MV, Sabirov RZ, Maeno E, Ando-Akatsuka Y, Bessonova SV, Okada Y (2005) Cells die with increased cytosolic ATP during apoptosis: a bioluminescence study with intracellular luciferase. Cell Death Differ 12:1390–1397

    Article  PubMed  CAS  Google Scholar 

  8. Borner C (2003) The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 39:615–647

    Article  PubMed  CAS  Google Scholar 

  9. Annis MG, Yethon JA, Leber B, Andrews DW (2004) There is more to life and death than mitochondria: Bcl-2 proteins at the endoplasmic reticulum. Biochim Biophys Acta 1644:115–123

    Article  PubMed  CAS  Google Scholar 

  10. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251

    Article  PubMed  CAS  Google Scholar 

  11. Kane DJ, Ord T, Anton R, Bredesen DE (1995) Expression of bcl-2 inhibits necrotic neural cell death. J Neurosci Res 40:269–275

    Article  PubMed  CAS  Google Scholar 

  12. Ellerby LM, Ellerby HM, Park SM, Holleran AL, Murphy AN, Fiskum G, Kane DJ, Testa MP, Kayalar C, Bredesen DE (1996) Shift of the cellular oxidation-reduction potential in neural cells expressing Bcl-2. J Neurochem 67:1259–1267

    Article  PubMed  CAS  Google Scholar 

  13. Mirkovic N, Voehringer DW, Story MD, McConkey DJ, McDonnell TJ, Meyn RE (1997) Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols. Oncogene 15:1461–1470

    Article  PubMed  CAS  Google Scholar 

  14. Amstad PA, Liu H, Ichimiya M, Berezesky IK, Trump BF, Buhimschi IA, Gutierrez PL (2001) BCL-2 is involved in preventing oxidant-induced cell death and in decreasing oxygen radical production. Redox Rep 6:351–362

    Article  PubMed  CAS  Google Scholar 

  15. Skarnes RC (1970) L-amino-acid oxidase, a bactericidal system. Nature 225:1072–1073

    Article  PubMed  CAS  Google Scholar 

  16. Zhang YJ, Wang JH, Lee WH, Wang Q, Liu H, Zheng YT, Zhang Y (2003) Molecular characterization of Trimeresurus stejnegeri venom L-amino acid oxidase with potential anti-HIV activity. Biochem Biophys Res Commun 309:598–604

    Article  PubMed  CAS  Google Scholar 

  17. Kanzawa N, Shintani S, Ohta K, Kitajima S, Ehara T, Kobayashi H, Kizaki H, Tsuchiya T (2004) Achacin induces cell death in HeLa cells through two different mechanisms. Arch Biochem Biophys 422:103–109

    Article  PubMed  CAS  Google Scholar 

  18. Murakawa M, Jung SK, Iijima K, Yonehara S (2001) Apoptosis-inducing protein, AIP, from parasite-infected fish induces apoptosis in mammalian cells by two different molecular mechanisms. Cell Death Differ 8:298–307

    Article  PubMed  CAS  Google Scholar 

  19. Suhr SM, Kim DS (1996) Identification of the snake venom substance that induces apoptosis. Biochem Biophys Res Commun 224:134–139

    Article  PubMed  CAS  Google Scholar 

  20. Ali SA, Stoeva S, Abbasi A, Alam JM, Kayed R, Faigle M, Neumeister B, Voelter W (2000) Isolation, structural, and functional characterization of an apoptosis-inducing L-amino acid oxidase from leaf-nosed viper (Eristocophis macmahoni) snake venom. Arch Biochem Biophys 384:216–226

    Article  PubMed  CAS  Google Scholar 

  21. Zeller AE (1977) Snake venom action: are enzymes involved in it? Experientia 33:143–150

    Article  PubMed  CAS  Google Scholar 

  22. Ehara T, Kitajima S, Kanzawa N, Tamiya T, Tsuchiya T (2002) Antimicrobial action of achacin is mediated by L-amino acid oxidase activity. FEBS Lett 531:509–512

    Article  PubMed  CAS  Google Scholar 

  23. Iijima R, Kisugi J, Yamazaki M (2003) L-amino acid oxidase activity of an antineoplastic factor of a marine mollusk and its relationship to cytotoxicity. Dev Comp Immunol 27:505–512

    Article  PubMed  CAS  Google Scholar 

  24. Torii S, Naito M, Tsuruo T (1997) Apoxin I, a novel apoptosis-inducing factor with L-amino acid oxidase activity purified from Western diamondback rattlesnake venom. J Biol Chem 272:9539–9542

    Article  PubMed  CAS  Google Scholar 

  25. Pawelek PD, Cheah J, Coulombe R, Macheroux P, Ghisla S, Vrielink A (2000) The structure of L-amino acid oxidase reveals the substrate trajectory into an enantiomerically conserved active site. Embo J 19:4204–4215

    Article  PubMed  CAS  Google Scholar 

  26. Geyer A, Fitzpatrick TB, Pawelek PD, Kitzing K, Vrielink A, Ghisla S, Macheroux P (2001) Structure and characterization of the glycan moiety of L-amino-acid oxidase from the Malayan pit viper Calloselasma rhodostoma. Eur J Biochem 268:4044–4053

    Article  PubMed  CAS  Google Scholar 

  27. von Gunten S, Yousefi S, Seitz M, Jakob SM, Schaffner T, Seger R, Takala J, Villiger PM, Simon HU (2005) Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment. Blood 106:1423–1431

    Article  PubMed  CAS  Google Scholar 

  28. Macheroux P, Seth O, Bollschweiler C, Schwarz M, Kurfurst M, Au LC, Ghisla S (2001) L-amino-acid oxidase from the Malayan pit viper Calloselasma rhodostoma. Comparative sequence analysis and characterization of active and inactive forms of the enzyme. Eur J Biochem 268:1679–1686

    Article  PubMed  CAS  Google Scholar 

  29. Bross P, Engst S, Strauss AW, Kelly DP, Rasched I, Ghisla S (1990) Characterization of wild-type and an active site mutant of human medium chain acyl-CoA dehydrogenase after expression in Escherichia coli. J Biol Chem 265:7116–7119

    PubMed  CAS  Google Scholar 

  30. Coles CJ, Edmondson DE, Singer TP (1977) Reversible inactivation of L-amino acid oxidase. Properties of the three conformational forms. J Biol Chem 252:8035–8039

    PubMed  CAS  Google Scholar 

  31. Aminoff D (1961) Methods for the quantitative estimation of N-acetylneuraminic acid and their application to hydrolysates of sialomucoids Biochem J 81:384–392

    PubMed  CAS  Google Scholar 

  32. Nisizawa K, Pigman W (1959) The composition and properties of the mucin clot from cattle submaxillary glands. Arch Oral Biol 1:161–170

    Article  PubMed  CAS  Google Scholar 

  33. Orlov SN, Pchejetski D, Taurin S, Thorin-Trescases N, Maximov GV, Pshezhetsky AV, Rubin AB, Hamet P (2004) Apoptosis in serum-deprived vascular smooth muscle cells: evidence for cell volume-independent mechanism. Apoptosis 9:55–66

    Article  PubMed  CAS  Google Scholar 

  34. Leicht M, Marx G, Karbach D, Gekle M, Kohler T, Zimmer HG (2003) Mechanism of cell death of rat cardiac fibroblasts induced by serum depletion. Mol Cell Biochem 251:119–126

    Article  PubMed  CAS  Google Scholar 

  35. Curti B, Ronchi S, Branzoli U, Ferri G, Williams CH Jr (1973) Improved purification, amino acid analysis and molecular weight of homogenous D-amino acid oxidase from pig kidney. Biochim Biophys Acta 327:266–273

    PubMed  CAS  Google Scholar 

  36. Pollegioni L, Molla G, Campaner S, Martegani E, Pilone MS (1997) Cloning, sequencing and expression in E. coli of a D-amino acid oxidase cDNA from Rhodotorula gracilis active on cephalosporin C. J Biotechnol 58:115–123

    Article  PubMed  CAS  Google Scholar 

  37. Voehringer DW, Meyn RE (2000) Redox aspects of Bcl-2 function. Antioxid Redox Signal 2:537–550

    Article  PubMed  CAS  Google Scholar 

  38. Schinzel A, Kaufmann T, Borner C (2004) Bcl-2 family members: integrators of survival and death signals in physiology and pathology [corrected]. Biochim Biophys Acta 1644:95–105

    Article  PubMed  CAS  Google Scholar 

  39. Tsujimoto Y, Shimizu S, Eguchi Y, Kamiike W, Matsuda H (1997) Bcl-2 and Bcl-xL block apoptosis as well as necrosis: possible involvement of common mediators in apoptotic and necrotic signal transduction pathways. Leukemia 11 (Suppl 3):380–382

    PubMed  Google Scholar 

  40. Single B, Leist M, Nicotera P (2001) Differential effects of bcl-2 on cell death triggered under ATP-depleting conditions. Exp Cell Res 262:8–16

    Article  PubMed  CAS  Google Scholar 

  41. Choi WS, Lee EH, Chung CW, Jung YK, Jin BK, Kim SU, Oh TH, Saido TC, Oh YJ (2001) Cleavage of Bax is mediated by caspase-dependent or -independent calpain activation in dopaminergic neuronal cells: protective role of Bcl-2. J Neurochem 77:1531–1541

    Article  PubMed  CAS  Google Scholar 

  42. Davies KJ (1999) The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress. IUBMB Life 48:41–47

    PubMed  CAS  Google Scholar 

  43. Ge X, Fu YM, Li YQ, Meadows GG (2002) Activation of caspases and cleavage of Bid are required for tyrosine and phenylalanine deficiency-induced apoptosis of human A375 melanoma cells. Arch Biochem Biophys 403:50–58

    Article  PubMed  CAS  Google Scholar 

  44. Torii S, Yamane K, Mashima T, Haga N, Yamamoto K, Fox JW, Naito M, Tsuruo T (2000) Molecular cloning and functional analysis of apoxin I, a snake venom-derived apoptosis-inducing factor with L-amino acid oxidase activity. Biochemistry 39:3197–3205

    Article  PubMed  CAS  Google Scholar 

  45. Suhr SM, Kim DS (1999) Comparison of the apoptotic pathways induced by L-amino acid oxidase and hydrogen peroxide. J Biochem (Tokyo) 125:305–309

    CAS  Google Scholar 

  46. Dorland RB, Middlebrook JL, Leppla SH (1979) Receptor-mediated internalization and degradation of diphtheria toxin by monkey kidney cells. J Biol Chem 254:11337–11342

    PubMed  CAS  Google Scholar 

  47. Middlebrook JL, Dorland RB, Leppla SH. Effects of lectins on the interaction of diphtheria toxin with mammalian cells (1979) Exp Cell Res 121:95–101

    Article  PubMed  CAS  Google Scholar 

  48. Morris RE, Gerstein AS, Bonventre PF, Saelinger CB (1985) Receptor-mediated entry of diphtheria toxin into monkey kidney (Vero) cells: electron microscopic evaluation. Infect Immun 50:721–727

    PubMed  CAS  Google Scholar 

  49. Keen JH, Maxfield FR, Hardegree MC, Habig WH (1982) Receptor-mediated endocytosis of diphtheria toxin by cells in culture. Proc Natl Acad Sci USA 79:2912–2916

    Article  PubMed  CAS  Google Scholar 

  50. Varki A (1997) Sialic acids as ligands in recognition phenomena. Faseb J 11:248–255

    PubMed  CAS  Google Scholar 

  51. Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC (2003) Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein. J Biol Chem 278:31007–31019

    Article  PubMed  CAS  Google Scholar 

  52. Crocker PR, Varki A (2001) Siglecs, sialic acids and innate immunity. Trends Immunol 22:337–342

    Article  PubMed  CAS  Google Scholar 

  53. Crocker PR, Zhang J (2002) New I-type lectins of the CD 33-related siglec subgroup identified through genomics. Biochem Soc Symp 83–94

  54. Varki A (1992) Selectins and other mammalian sialic acid-binding lectins. Curr Opin Cell Biol 4:257–266

    Article  PubMed  CAS  Google Scholar 

  55. Kelm S, Schauer R (1997) Sialic acids in molecular and cellular interactions. Int Rev Cytol 175:137–240

    Article  PubMed  CAS  Google Scholar 

  56. Zhang H, Yang Q, Sun M, Teng M, Niu L (2004) Hydrogen peroxide produced by two amino acid oxidases mediates antibacterial actions. J Microbiol 42:336–339

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biochemistry Research Group, University of Konstanz, D-78464, Konstanz, Germany

    Sudharsana Rao Ande, Phaneeswara Rao Kommoju & Sandro Ghisla

  2. Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78464, Konstanz, Germany

    Elisa Ferrando-May

  3. Institute of Food Chemistry and Technology, Graz University of Technology, Petersgasse 12, A-8010, Graz, Austria

    Sigrid Draxl & Michael Murkovic

  4. Institute of Biochemistry, Graz University of Technology, Petersgasse 12, A-8010, Graz, Austria

    Peter Macheroux

Authors
  1. Sudharsana Rao Ande
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Phaneeswara Rao Kommoju
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sigrid Draxl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Murkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Macheroux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandro Ghisla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elisa Ferrando-May
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elisa Ferrando-May.

Additional information

S. R. Ande, P. R. Kommoju contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ande, S.R., Kommoju, P.R., Draxl, S. et al. Mechanisms of cell death induction by L-amino acid oxidase, a major component of ophidian venom. Apoptosis 11, 1439–1451 (2006). https://doi.org/10.1007/s10495-006-7959-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-006-7959-9

Keywords

Search

Navigation