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The Lysine-Specific Gingipain of Porphyromonas gingivalis

Importance to Pathogenicity and Potential Strategies for Inhibition
  • Tang Yongqing
  • Jan Potempa
  • Robert N. Pike
  • Lakshmi C. Wijeyewickrema
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 712)

Abstract

Periodontitis is a disease affecting the supporting structures of the teeth. The most severe forms of the disease result in tooth loss and have recently been strongly associated with systemic diseases, including cardiovascular and lung diseases and cancer. The disease is caused by biofilms of predominantly anaerobic bacteria. A major pathogen associated with severe, adult forms of the disease is Porphyromonas gingivalis. This organism produces potent cysteine proteases known as gingipains, which have specificity for cleavage after arginine or lysine residues. The lysine-specific gingipain, Kgp, appears to be the major virulence factor of this organism and here we describe its structure and function. We also discuss the inhibitors of the enzyme produced to date and the potential pathways to newer versions of such molecules that will be required to combat periodontitis.

Keywords

Cysteine Protease Tooth Loss Pathogenic Organism Porphyromonas Gingivalis Periodontal Pocket 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Brown LJ, John BA, Wall TP. The economics of periodontal diseases. Periodontol 2000.2002; 29:223–234.PubMedGoogle Scholar
  2. 2.
    Spencer AJ, Wright FAC, Brown DF et al. A socio-dental study of adult periodontal health: Melbourne 1985. Melbourne: The University of Melbourne, 1988.Google Scholar
  3. 3.
    Shultis WA, Weil EJ, Looker HC et al. Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes. Diabetes Care 2007; 30:306–311.PubMedGoogle Scholar
  4. 4.
    DeStefano F, Anda RF, Kahn HS et al. Dental disease and risk of coronary heart disease and mortality. Br Med J 1993; 306:688–691.Google Scholar
  5. 5.
    Jeffcoat MK, Hauth JC, Geurs NC et al. Periodontal disease and preterm birth: result of a pilot intervention study. J Periodontol 2003; 74:1214–1218.PubMedGoogle Scholar
  6. 6.
    Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1999; 70:793–802.PubMedGoogle Scholar
  7. 7.
    Shapira L, Ayalon S, Brenner T. Effects of Porphyromonas gingivalis on the central nervous system: Activation of glial cells and exacerbation of experimental autoimmune encephalomyelitis. J Periodontol 2002; 73:511–516.PubMedGoogle Scholar
  8. 8.
    Teng YT, Taylor GW, Scannapieco F et al. Periodontal health and systemic disorders. J Can Dent Assoc 2002; 68:188–192.PubMedGoogle Scholar
  9. 9.
    Mercado FB, Marshall RI, Bartold PM. Inter-relationship between rheumatoid arthritis and periodontal disease. A review. J Clin Periodontol 2003; 30:761–772.PubMedGoogle Scholar
  10. 10.
    Meyer MS, Joshipura K, Giovannucci E et al. A review of the relationship between tooth loss, periodontal disease and cancer. Cancer Cause Control 2008; 19:895–907.Google Scholar
  11. 11.
    Seymour GJ, Ford PJ, Cullinan MP et al. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect 2007; 13:3–10.PubMedGoogle Scholar
  12. 12.
    Socransky S, Haffajee A. Evidence of bacterial aetiology: a historical perspective. Periodontol 2000 1994; 5:7–25.PubMedGoogle Scholar
  13. 13.
    Armitage GC. Periodontal diagnoses and classification of periodontal diseases. Periodontol 2000 2004; 34:9–12.PubMedGoogle Scholar
  14. 14.
    Kinane DF. Causation and pathogenesis of periodontal diseases. Periodontol 2000 2001; 25:8–20.PubMedGoogle Scholar
  15. 15.
    Armitage GC. Classifyingperiodontal diseases—a long-standing dilemma. Periodontol 2000 2002; 30:9–23.PubMedGoogle Scholar
  16. 16.
    Haffajee AD, Socransky SS. Microbial etiological agents of destructive periodontal diseases. Periodontol 2000 1994; 5:78–111.PubMedGoogle Scholar
  17. 17.
    Fitzpatrick RE, Wijeyewickrema LC, Pike RN. The gingipains: scissors and glue of theperiodontalpathogen, Porphyrmonas gingivalis. Future Microbiol 2009; 4:471–487.PubMedGoogle Scholar
  18. 18.
    Kasuga Y, Ishihara K, Okuda K. Significance of detection of Porphyromonas gingivalis, Bacteroides forsythus and treponema denticola in periodontal pockets. Bull Tokyo Dent Coll 2000; 41:109–117.PubMedGoogle Scholar
  19. 19.
    Holt SC, Ebersole JL. Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia: the ‘red complex’, a prototype polybacterial pathogenic consortium in periodontitis. Periodontol 2000 2005; 38:72–122.PubMedGoogle Scholar
  20. 20.
    White D, Mayrand D. Association of oral bacteroides with gingivitis and adult periodontitis. J Periodontal Res 1981; 16:259–265.PubMedGoogle Scholar
  21. 21.
    Holt SC, Ebersole J, Felton J et al. Implantation of Bacteroides gingivalis in nonhuman primates initiates progression of periodontitis. Science 1988; 239:55–57.PubMedGoogle Scholar
  22. 22.
    Gibson FC, Genco CA. The genus Porphyromonas. In: The Prokaryote. New York: Springer, 2006:428–454.Google Scholar
  23. 23.
    Lamont RJ, Jenkinson HF. Life below the gum line: pathogenic mechanisms of Porphyromonas gingivalis. Microbiol Mol Biol Rev 1998; 62:1244–1263.PubMedGoogle Scholar
  24. 24.
    Mayrand D, Holt SC. Biology of asaccharolytic black-pigmented Bacteroides species. Microbiol Rev 1988; 52:134–152.PubMedGoogle Scholar
  25. 25.
    Smalley JW, Silver J, Marsh PJ et al. The periodontopathogen Porphyromonas gingivalis binds iron protoporphyrin IX in the m-oxo dimeric form: an oxidative buffer and possible pathogenic mechanism. Biochem J 1998; 331:681–685.PubMedGoogle Scholar
  26. 26.
    Shah HN, Williams RAD. Utilization of glucose and amino acids by Bacteroides intermedius and Bacteroides gingivalis. Curr Microbiol 1987; 15:241–246.Google Scholar
  27. 27.
    van Steenbergen TJM, Kastelein P, Touw JJA et al. Virulence of black-pigmented Bacteroides strains from periodontal pockets and other sites in experimentally induced skin lesions in mice. J Periodont Res 1982; 17:41–49.PubMedGoogle Scholar
  28. 28.
    Amano A, Shizukuishi S, Horie H et al. Binding of Porphyromonas gingivalis fimbriae to proline-rich glycoproteins in parotid saliva via a domain shared by major salivary components. Infect Immun 1998; 66:2072–2077.PubMedGoogle Scholar
  29. 29.
    Holt SC, Kesavaku L, Walker S et al. Virulence factors of Porphyromonas gingivalis. Periodontol 2000 1999; 20:168–238.PubMedGoogle Scholar
  30. 30.
    Lamont RJ, Yilmaz O. In or out: the invasiveness of oral bacteria. Periodontol 2000 2002; 30:61–69.PubMedGoogle Scholar
  31. 31.
    Lamont RJ, Bevan CA, Gil S et al. Involvement of Porphyromonas gingivalis fimbriae in adherence to Streptococcus gordonii. Oral Microbiol Immunol 1993; 8:272–276.PubMedGoogle Scholar
  32. 32.
    Isogai H, Isogai E, Yoshimura F et al. Specific inhibition of adherence of an oral strain of Bacteroides gingivalis 381 to epithelial cells by monoclonal antibodies against the bacterial fimbriae. Arch Oral Biol 1988; 33:479–485.PubMedGoogle Scholar
  33. 33.
    Birkedal-Hansen H, Taylor RE, Zambon JJ et al. Characterization of collagenolytic activity from strains of Bacteroides gingivalis. J Periodont Res 1988; 23:258–264.PubMedGoogle Scholar
  34. 34.
    Bleeg HS, Polenik P. Sodium dodecyl sulfate potentiates collagen degradation by proteases from Porphyromonas gingivalis. FEMS Microbiol Ecol 1991; 85:125–132.Google Scholar
  35. 35.
    Kesavalu L, Holt SC, Ebersole JL. Trypsin-like protease activity of Porphyromonas gingivalis as a potential virulence factor in the murine lesion model. Microb Pathog 1996; 20:1–10.PubMedGoogle Scholar
  36. 36.
    Chen Z, Potempa J, Polanowski A et al. Purification and characterization of a 50-kDa cysteine proteinase (gingipain) from Porphyromonas gingivalis. J Biol Chem 1992; 267:18896–18901.PubMedGoogle Scholar
  37. 37.
    Pike R, McGraw W, Potempa J et al. Lysine-and arginine-specific proteinases from Porphyromonas gingivalis. Isolation, characterization and evidence for the existence of complexes with hemagglutinins. J Biol Chem 1994; 269:406–411.PubMedGoogle Scholar
  38. 38.
    Kesavalu L, Holt SC, Ebersole JL. Porphyromonas gingivalis virulence in a murine lesion model: effects of immune alterations. Microb Pathog 1997; 23:317–326.PubMedGoogle Scholar
  39. 39.
    McKee AS, McDermid AS, Wait R et al. Isolation of colonial variants of Bacteroides gingivalis W50 with reduced virulence. J Med Microbiol 1988; 27:59–64.PubMedGoogle Scholar
  40. 40.
    Pavloff N, Pemberton PA, Potempa J et al. Molecular cloning and characterization of Porphyromonas gingivalis lysine-specific gingipain. J Biol Chem 1997; 272:1595–1600.PubMedGoogle Scholar
  41. 41.
    Potempa J, Pike R, Travis J. Titration and mapping of the active site of cysteine proteinases from Porphyromonas gingivalis (gingipain) using peptidyl chloromethanes. J Biol Chem 1997; 378:223–230.Google Scholar
  42. 42.
    Curtis MA, Aduse-Opoku J, Rangarajan M. Cysteine Proteases of Porphyromonas Gingivalis. Crit Rev Oral Biol M 2001; 12:192–216.Google Scholar
  43. 43.
    Curtis MA, Kuramitsu HK, Lantz M et al. Molecular genetics and nomenclature of proteases of Porphyromonas gingivalis. J Periodontal Res 1999; 34:464–472.PubMedGoogle Scholar
  44. 44.
    Tokuda M, Duncan M, Cho MI et al. Role of Porphyromonas gingivalis protease activity in colonization of oral surfaces. Infect Immun 1996; 64:4067–4073.PubMedGoogle Scholar
  45. 45.
    Tokuda M, Karunakaran T, Duncan M et al. Role of Arg-gingipain A in virulence of Porphyromonas gingivalis. Infect Immun 1998; 66:1159–1166.PubMedGoogle Scholar
  46. 46.
    Shi Y, Ratnayake DB, Okamoto K et al. Genetic analyses of proteolysis, hemoglobin binding and hemagglutination of Porphyromonas gingivalis: construction of mutants with a combination of rgpA, rgpB, kgp and hagA. J Biol Chem 1999; 274:17955–17960.PubMedGoogle Scholar
  47. 47.
    O’Brien-Simpson NM, Paolini RA, Hoffmann B et al. Role of RgpA, RgpB and Kgp proteinases in virulence of Porphyromonas gingivalis W50 in a murine lesion model. Infect Immun 2001; 69:7527–7534.PubMedGoogle Scholar
  48. 48.
    Pathirana RD, O’Brien-Simpson NM, Brammar GC et al. Kgp and RgpB, but not RgpA, are important for Porphyromonas gingivalis virulence in the murine periodontitis model. Infect Immun 2007; 75:1436–1442.PubMedGoogle Scholar
  49. 49.
    O’Brien-Simpson NM, Veith PD, Dashper SG et al. Porphyromonas gingivalis gingipains: the molecular teeth of a microbial vampire. Curr Protein Pept Sci 2003; 4:409–426.Google Scholar
  50. 50.
    Barua PK, Dyer DW, Neiders ME. Effect of iron limitation on Bacteroides gingivalis. Oral MicroImmunol 1990; 5:263–268.Google Scholar
  51. 51.
    Shizukuishi S, Tazaki K, Inoshita E et al. Effect of concentration of compounds containing iron on the growth of Porphyromonas gingivalis. FEMS Microbiol Lett 1995; 131:313–317.PubMedGoogle Scholar
  52. 52.
    Lewis JP, Dawson JA, Hannis JC et al. Hemoglobinase activity of the lysine gingipain protease (Kgp) of Porphyromonas gingivalis. J Bacteriol 1999; 181:4905–4913.PubMedGoogle Scholar
  53. 53.
    Okamoto K, Nakayama K, Kadowaki T et al. Involvement of a lysine-specific cysteineproteinase in hemoglobin adsorpti on and heme accumulation by Porphyromonas gingivalis. J Biol Chem 1998; 273:21225–21231.PubMedGoogle Scholar
  54. 54.
    Pike RN, Potempa J, McGraw W et al. Characterization of the binding activities of proteinase-adhesin complexes from Porphyromonas gingivalis. J Bacteriol 1996; 178:2876–2882.PubMedGoogle Scholar
  55. 55.
    Ryan ME, Golub LM. Modulation of matrix metalloproteinase activities in periodontitis as a treatment strategy. Periodontol 2000 2000; 24:226–238.PubMedGoogle Scholar
  56. 56.
    Decarlo Jr AA, Windsor LJ, Bodden MK et al. Activation and novel processing of matrix metalloproteinases by a thiol-protease from the oral anaerobe Porphyromonas gingivalis. J Dent Res 1997; 76:1260–1270.PubMedGoogle Scholar
  57. 57.
    Imamura T, Potempa J, Pike RN et al. Effect of free and vesicle-bound cysteine proteinases of Porphyromonas gingivalis on plasma clot formation: implications for bleeding tendency at periodontitis sites. Infect Immun 1995; 63:4877–4882.PubMedGoogle Scholar
  58. 58.
    Fletcher J, Reddi K, Poole S et al. Interactions between periodontopathogenic bacteria and cytokines. J Periodont Res 1997; 32:200–205.PubMedGoogle Scholar
  59. 59.
    Yun PLW, DeCarlo AA, Hunter N. Modulation of major histocompatibility complex protein expression by human gamma interferon mediated by cysteine proteinase-adhesin polyproteins of Porphyromonas gingivalis. Infect Immun 1999; 67:2986–2995.PubMedGoogle Scholar
  60. 60.
    Oleksy A, Banbula A, Bugno M et al. Proteolysis of interleukin-6 receptor (IL-6R) by Porphyromonas gingivalis cysteine proteinases (gingipains) inhibits interleukin-6-mediated cell activation. Microb Pathog 2002; 32:173–181.PubMedGoogle Scholar
  61. 61.
    Yun PLW, Decarlo AA, Collyer C et al. Hydrolysis of interleukin-12 by Porphyromonas gingivalis major cysteine proteinases may affect local gamma interferon accumulation and the Th1 or Th2 T-cell phenotype in periodontitis. Infect Immun 2001; 69:5650–5660.PubMedGoogle Scholar
  62. 62.
    Liu RK, Cao CF, Meng HX et al. Polymorphonuclear neutrophils and their mediators in gingival tissues from generalized aggressive periodontitis. J Periodontol 2001; 72:1545–1553.PubMedGoogle Scholar
  63. 63.
    Sugawara S, Nemoto E, Tada H et al. Proteolysis of human monocyte CD 14 by cysteine proteinases (gingipains) from Porphyromonas gingivalis leading to lipopolysaccharide hyporesponsiveness. J Immunol 2000; 165:411–418.PubMedGoogle Scholar
  64. 64.
    Kitamura Y, Yoneda M, Imamura T et al. Gingipains in the culture supernatant of Porphyromonas gingivalis cleave CD4 and CD8 on human T-cells. J Periodont Res 2002; 37:464–468.PubMedGoogle Scholar
  65. 65.
    Kitamura Y, Hirofuji T, Yoneda M et al. Cleavage of surface proteins on human T-cells by the culture supernatant of Porphyromonas gingivalis 381. Dent J 2000; 36:109–112.Google Scholar
  66. 66.
    Fishburn CS, Slaney JM, Carman RJ et al. Degradation of plasma proteins by the trypsin-like enzyme of Porphyromonas gingivalis and inhibition of protease activity by a serine protease inhibitor of human plasma. Oral Microbiol Immunol 1991; 6:209–215.PubMedGoogle Scholar
  67. 67.
    Uehara A, Imamura T, Potempa J et al. Gingipains from Porphyromonas gingivalis synergistically induce the production of proinflammatory cytokines through protease-activated receptors with Toll-like receptor and NOD 1/2 ligands in human monocytic cells. Cell Microbiol 2008; 10:1181–1189.PubMedGoogle Scholar
  68. 68.
    Huang GTJ, Kim D, Lee JKH et al. Interleukin-8 and intercellular adhesion molecule 1 regulation in oral epithelial cells by selected periodontal bacteria: multiple effects of Porphyromonas gingivalis via antagonistic mechanisms. Infect Immun 2001; 69:1364–1372.PubMedGoogle Scholar
  69. 69.
    Pavloff N, Potempa J, Pike RN et al. Molecular cloning and structural characterization of the arg-gingipain proteinase of Porphyromonas gingivalis. J Biol Chem 1995; 270:1007–1010.PubMedGoogle Scholar
  70. 70.
    Mikolajczyk-Pawlinska J, Kordula T, Pavloff N et al. Genetic variation of Porphyromonas gingivalis genes encoding gingipains, cysteine proteinases with arginine or lysine specificity. Biol Chem 1998; 379:205–211.PubMedGoogle Scholar
  71. 71.
    Potempa J, Sroka A, Imamura T et al. Gingipains, the major cysteine proteinases and virulence factors of Porphyromonas gingivalis: Structure, function and assembly of multidomain protein complexes. Curr Protein Pept Sci 2003; 6:443–450.Google Scholar
  72. 72.
    Slakeski N, Cleal SM, Bhogal PS et al. Characterization of a Porphyromonas gingivalis gene prtK that encodes a lysine-specific thiol proteinase and multiple adhesins. Oral Microbiol Immunol 1999; 14:92–97.PubMedGoogle Scholar
  73. 73.
    Slakeski N, Bhogal PS, O’Brien-Simpson NM et al. Characterization of asecond cell-associated Arg-specific cysteine proteinase of Porphyromonas gingivalis and identification of an adhesin binding motif involved in association of the prtR and prtK proteinases and adhesins into large complexes. Microbiol 1998; 144:1583–1592.Google Scholar
  74. 74.
    O’Brien-Simpson NM, Paolini RA, Reynolds EC. RgpA-Kgppeptide-based immunogens provide protection against Porphyromonas gingivalis challenge in a murine lesion model. Infect Immun 2000; 68:4055–4063.PubMedGoogle Scholar
  75. 75.
    O’Brien-Simpson NM, Pathirana RD, Paolini RA et al. An immune response directed to proteinase and adhesin functional epitopes protects against Porphyromonas gingivalis-induced periodontal bone loss. J Immunol 2005; 175:3980–3989.PubMedGoogle Scholar
  76. 76.
    Barkocy-Gallagher GA, Han N, Patti JM et al. Analysis of the prtP gene encoding porphypain, a cysteine proteinase of Porphyromonas gingivalis. J Bacteriol 1996; 178:2734–2741.PubMedGoogle Scholar
  77. 77.
    Lewis JP, Macrina FL. IS195, an insertion sequence-like element associated with protease genes in Porphyromonas gingivalis. Infect Immun 1998; 66:3035–3042.PubMedGoogle Scholar
  78. 78.
    Okamoto K, Kadowaki T, Nakayama K et al. Cloning and sequencing of the gene encoding a novel lysine-specific cysteine proteinase (lys-gingipain) in Porphyromonas gingivalis: Structural relationship with the arginine-specific cysteine proteinase (arg-gingipain). J Biochem 1996; 120:398–406.PubMedGoogle Scholar
  79. 79.
    Li N, Yun P, Nadkarni MA et al. Structure determination and analysis of a haemolytic adhesin domain from Porphyromonas gingivalis. Mol Microbiol 2010; 76:861–873.PubMedGoogle Scholar
  80. 80.
    Bhogal PS, Slakeski N, Reynolds E. Characterization of a cell-associated, protein complex of Porphyromonas gingivalis W50 composed of Arg-and Lys-specific cysteine proteinases and adhesins. Microbiol 1997; 143:2485–2495.Google Scholar
  81. 81.
    Curtis MA, Thickett A, Slaney JM et al. Variable carbohydrate modifications to the catalytic chains of the RgpA and RgpB proteases of Porphyromonas gingivalis W50. Infect Immun 1999; 67:3816–3823.PubMedGoogle Scholar
  82. 82.
    Rangarajan M, Smith SJM, U S et al. Biochemical characterization of the arginine-specific proteases of Porphyromonas gingivalis W50 suggests a common precursor. Biochem J 1997; 323:701–709.PubMedGoogle Scholar
  83. 83.
    Seers CA, Slakeski N, Veith PD et al. The RgpB C-terminal domain has a role in attachment of RgpB to the outer membrane and belongs to a novel C-terminal-domain family found in Porphyromonas gingivalis. J Bacteriol 2006; 188:6376–6386.PubMedGoogle Scholar
  84. 84.
    Pathirana RD, O’Brien-Simpson NM, Veith PD et al. Characterization of proteinase-adhesin complexes of Porphyromonas gingivalis. Microbiol 2006; 152:2381–2394.Google Scholar
  85. 85.
    Fujimura S, Nakamura T. Isolation and characterization of a protease from Bacteroides gingivalis. Infect Immun 1987; 55:716–720.PubMedGoogle Scholar
  86. 86.
    Bedi GS. Comparative study of four proteases from spent culture media of Porphyromonas gingivalis (FAY-19M-1). Prep Biochem 1995; 25:133–154.PubMedGoogle Scholar
  87. 87.
    Takii R, Kadowaki T, Baba A et al. A functional virulence complex composed of gingipains, adhesins and lipopolysaccharide shows high affinity to host cells and matrix proteins and escapes recognition by host immune systems. Infect Immun 2005; 73:883–893.PubMedGoogle Scholar
  88. 88.
    Shoji M, Ratnayake DB, Shi Y et al. Construction and characterization of a nonpigmented mutant of Porphyromonas gingivalis: cell surface polysaccharide as an anchorage for gingipains. Microbiol 2002; 148:1183–1191.Google Scholar
  89. 89.
    Aduse-Opoku J, Davies NN, Gallagher A et al. Generation of Lys-gingipainprotease activity in Porphyromonas gingivalis W50 is independent of Arg-gingipain protease activities. Microbiol 2000; 146:1933–1940.Google Scholar
  90. 90.
    Potempa J, Banbula A, Travis J. Role of bacterial proteinases in matrix destruction and modulation of host responses. Periodontol 2000 2000; 24:153–192.PubMedGoogle Scholar
  91. 91.
    Okamoto K, Misumi Y, Kadowaki T et al. Structural characterization of argingipain, a novel arginine-specific cysteine proteinase as a major periodontal pathogenic factor from Porphyromonas gingivalis. Arch Biochem Biophys 1995; 316:917–925.PubMedGoogle Scholar
  92. 92.
    Eichinger A, Beisel HG, Jacob U et al. Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold. EMBO J 1999; 18:5453–5462.PubMedGoogle Scholar
  93. 93.
    Schechter I, Berger A. On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 1967; 27:157–162.PubMedGoogle Scholar
  94. 94.
    Chen JM, Rawlings ND, Stevens RA et al. Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases. FEBS Lett 1998; 441:361–365.PubMedGoogle Scholar
  95. 95.
    Howard AE, Kollman PA. OH-versus SH-nucleophilic attack on amides: dramatically different gas-phase and solvation energetics. J Am Chem Soc 1988; 110:7195–7200.Google Scholar
  96. 96.
    Arad D, Langridge R, Kollman PA. A simulation of the sulfur attack in the catalytic pathway of papain using molecular mechanics and semiempirical quantum mechanics. J Am Chem Soc 1988; 112:491–502.Google Scholar
  97. 97.
    Shi Y. Aaspase activation: revisiting the induced proximity model. Cell 2004; 117:855–858.PubMedGoogle Scholar
  98. 98.
    Albeck A, Kliper S. Mechanism of cysteine protease inactivation by peptidyl epoxides. Biochem J 1997; 322:879–884.PubMedGoogle Scholar
  99. 99.
    Abe N, Kadowaki T, Okamoto K et al. Biochemical and functional properties of Lysine-specific cysteine proteinase (Lys-gingipain) as a virulence factor of Porphyromonas gingivalis in periodontal disease. J Biochem 1998; 123:305–312.PubMedGoogle Scholar
  100. 100.
    Abe N, Baba A, Kadowaki T et al. Design and synthesis of sensitive fluorogenic substrates specific for Lys-gingipain. J Biochem 2000; 128:877–881.PubMedGoogle Scholar
  101. 101.
    Gusman H, Travis J, Helmerhorst EJ et al. Salivary histatin 5 is an inhibitor of both host and bacterial enzymes implicated in periodontal disease. Infect Immun 2001; 69:1402–1408.PubMedGoogle Scholar
  102. 102.
    Snipas SJ, Stennicke HR, Riedl S et al. Inhibition of distant caspase homologues by natural caspase inhibitors. J Biochem 2001; 357:575–580.Google Scholar
  103. 103.
    Bodet C, Piché M, Chandad F et al. Inhibition of periodontopathogen-derived proteolytic enzymes by a high-molecular-weight fraction isolated from cranberry. J Antimicrob Chemother 2006; 57:685–690.PubMedGoogle Scholar
  104. 104.
    Yamanaka A, Kouchi T, Kasai K et al. Inhibitory effect of cranberry polyphenol on biofilm formation and cysteine proteases of Porphyromonas gingivalis. J Periodont Res 2007; 42:589–592.PubMedGoogle Scholar
  105. 105.
    Bania J, Kubiak A, Wojtachnio K et al. Pancreatic secretory trypsin inhibitor acts as an effective inhibitor of cysteine proteinases gingipains from Porphyromonas gingivalis. J Periodont Res 2008; 43:232–236.PubMedGoogle Scholar
  106. 106.
    Cronan CA, Potempa J, Travis J et al. Inhibition of Porphyromonas gingivalis proteinases (gingipains) by chlorhexidine: synergistic effect of Zn(II). Oral Microbiol Immunol 2006; 21:212–217.PubMedGoogle Scholar
  107. 107.
    Curtis MA, Aduse-Opoku J, Rangarajan M et al. Attenuation of the virulence of Porphyromonas gingivalis by using a specific synthetic Kgp protease inhibitor. Infect Immun 2002; 70:6968–6975.PubMedGoogle Scholar
  108. 108.
    Kadowaki T, Baba A, Abe N et al. Suppression of pathogenicity of Porphyromonas gingivalis by newly developed gingipain inhibitors. Mol Pharmacol 2004; 66:1599–1606.PubMedGoogle Scholar
  109. 109.
    Ekici OD, Götz MG, James KE et al. Aza-peptide Michael acceptors: a new class of inhibitors specific for caspases and other clan CD cysteine proteases. J Med Chem 2004; 47:1889–1892.PubMedGoogle Scholar
  110. 110.
    Białas A, Grembecka J, Krowarsch D et al. Exploring the Sn binding pockets in gingipains by newly developed inhibitors: structure-based design, chemistry and activity. J Med Chem 2006; 49:1744–1753.PubMedGoogle Scholar
  111. 111.
    Ally, N. The specificity of proteinase-adhesins from Porphyromonas gingivalis. PhD thesis. Melbourne: Monash University, 2003.Google Scholar
  112. 112.
    Thomas DA, Francis P, Smith C et al. A broad-spectrum fluorescence-based peptide library for the rapid identification of protease substrates. Proteomics 2006; 6:2112–2120.PubMedGoogle Scholar
  113. 113.
    Birkett AJ, Soler DF, Wolz RL et al. Determination of enzyme specificity in a complex mixture of peptide substrates by N-terminal sequence analysis. Anal Biochem 1991; 196:137–143.PubMedGoogle Scholar
  114. 114.
    Petithory JR, Masiarz FR, Kirsch JF et al. A rapid method for determination of endoproteinase substrate specificity: Specificity of the 3C proteinase from hepatitis A virus. Proc Natl Acad Sci USA 1991; 88:11510–11514.PubMedGoogle Scholar
  115. 115.
    Turk BE, Cantley LC. Using peptide libraries to identify optimal cleavage motifs for proteolytic enzymes. Methods 2004; 32:398–405.PubMedGoogle Scholar
  116. 116.
    Meldal M, Svendsen I, Breddam K et al. Portion-mixingpeptide libraries of quenched fluorogenic substrates for complete subsite mapping of endoprotease specificity. P Natl Acad Sci USA 1994; 91:3314–3318.Google Scholar
  117. 117.
    Leon S, Quarrell R, Lowe G. Evaluation of resins for on-bead screening: a study of papain and chymotrypsin specificity using PEGA-bound combinatorial peptide libraries. Bioorg Med Chem Lett 1998; 8:2997–3002.PubMedGoogle Scholar
  118. 118.
    Harris JL, Backes BJ, Leonetti F et al. Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries. P Natl Acad Sci USA 2000; 97:7754–7759.Google Scholar
  119. 119.
    Matthews DJ, Well JA. Substrate phage: selection of protease substrates by monovalent phage display. Science 1993; 260:1113–1117.PubMedGoogle Scholar
  120. 120.
    Deng SJ, Bickett DM, Mitchell JL et al. Substrate specificity of human collagenase 3 assessed using a phage-displayed peptide library. J Biol Chem 2000; 275:31422–31427.PubMedGoogle Scholar
  121. 121.
    Le Bonniec BF, Myles T, Johnson T et al. Characterization of the P2′ and P3′ specificities of thrombin using fluoresence-quenched substrates and mapping of the subsites by mutagenesis. Biochem 1996; 35:7114–7122.Google Scholar
  122. 122.
    Ally N, Whisstick JC, Sieprawska-Lupa M et al. Characterization of the specificity of Arginine-specific gingipain from Porphyromonas gingivalis reveals active site differences between different forms of the enzymes. Biochem 2003; 42:11693–11700.Google Scholar

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© Landes Bioscience and Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Tang Yongqing
    • 1
  • Jan Potempa
    • 2
  • Robert N. Pike
    • 1
  • Lakshmi C. Wijeyewickrema
    • 3
  1. 1.Department of Biochemistry and Molecular Biology and CRC for Oral Health SciencesMonash UniversityClaytonAustralia
  2. 2.Oral Health and Systemic Disease Research FacilityUniversity of Louisville School of DentistryLouisvilleUSA
  3. 3.Department of Microbiology, Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityKrakowPoland

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