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. 1998 Mar-Apr;71(2):63–73.

Structure, function and localization of Helicobacter pylori urease.

B E Dunn 1, S H Phadnis 1
PMCID: PMC2578883  PMID: 10378351

Abstract

Helicobacter pylori is the causative agent of most cases of gastritis. Once acquired, H. pylori establishes chronic persistent infection; it is this long-term infection that, is a subset of patients, leads to gastric or duodenal ulcer, gastric cancer or gastric MALT lymphoma. All fresh isolates of H. pylori express significant urease activity, which is essential to survival and pathogenesis of the bacterium. A significant fraction of urease is associated with the surface of H. pylori both in vivo and in vitro. Surface-associated urease is essential for H. pylori to resist exposure to acid in the presence of urea. The mechanism whereby urease becomes associated with the surface of H. pylori is unique. This process, which we term "altruistic autolysis," involves release of urease (and other cytoplasmic proteins) by genetically programmed autolysis with subsequent adsorption of the released urease onto the surface of neighboring intact bacteria. To our knowledge, this is the first evidence of essential communal behavior in pathogenic bacteria; such behavior is crucial to understanding the pathogenesis of H. pylori.

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Selected References

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  1. Andrutis K. A., Fox J. G., Schauer D. B., Marini R. P., Murphy J. C., Yan L., Solnick J. V. Inability of an isogenic urease-negative mutant stain of Helicobacter mustelae to colonize the ferret stomach. Infect Immun. 1995 Sep;63(9):3722–3725. doi: 10.1128/iai.63.9.3722-3725.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bauerfeind P., Garner R. M., Mobley L. T. Allelic exchange mutagenesis of nixA in Helicobacter pylori results in reduced nickel transport and urease activity. Infect Immun. 1996 Jul;64(7):2877–2880. doi: 10.1128/iai.64.7.2877-2880.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blanchard T. G., Czinn S. J., Maurer R., Thomas W. D., Soman G., Nedrud J. G. Urease-specific monoclonal antibodies prevent Helicobacter felis infection in mice. Infect Immun. 1995 Apr;63(4):1394–1399. doi: 10.1128/iai.63.4.1394-1399.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blaser M. J. Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation. Gastroenterology. 1992 Feb;102(2):720–727. doi: 10.1016/0016-5085(92)90126-j. [DOI] [PubMed] [Google Scholar]
  5. Bode G., Malfertheiner P., Lehnhardt G., Nilius M., Ditschuneit H. Ultrastructural localization of urease of Helicobacter pylori. Med Microbiol Immunol. 1993 Nov;182(5):233–242. doi: 10.1007/BF00579622. [DOI] [PubMed] [Google Scholar]
  6. Clayton C. L., Pallen M. J., Kleanthous H., Wren B. W., Tabaqchali S. Nucleotide sequence of two genes from Helicobacter pylori encoding for urease subunits. Nucleic Acids Res. 1990 Jan 25;18(2):362–362. doi: 10.1093/nar/18.2.362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clyne M., Drumm B. The urease enzyme of Helicobacter pylori does not function as an adhesin. Infect Immun. 1996 Jul;64(7):2817–2820. doi: 10.1128/iai.64.7.2817-2820.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Corthésy-Theulaz I., Porta N., Glauser M., Saraga E., Vaney A. C., Haas R., Kraehenbuhl J. P., Blum A. L., Michetti P. Oral immunization with Helicobacter pylori urease B subunit as a treatment against Helicobacter infection in mice. Gastroenterology. 1995 Jul;109(1):115–121. doi: 10.1016/0016-5085(95)90275-9. [DOI] [PubMed] [Google Scholar]
  9. Craig P. M., Territo M. C., Karnes W. E., Walsh J. H. Helicobacter pylori secretes a chemotactic factor for monocytes and neutrophils. Gut. 1992 Aug;33(8):1020–1023. doi: 10.1136/gut.33.8.1020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cuenca R., Blanchard T. G., Czinn S. J., Nedrud J. G., Monath T. P., Lee C. K., Redline R. W. Therapeutic immunization against Helicobacter mustelae in naturally infected ferrets. Gastroenterology. 1996 Jun;110(6):1770–1775. doi: 10.1053/gast.1996.v110.pm8964402. [DOI] [PubMed] [Google Scholar]
  11. Cussac V., Ferrero R. L., Labigne A. Expression of Helicobacter pylori urease genes in Escherichia coli grown under nitrogen-limiting conditions. J Bacteriol. 1992 Apr;174(8):2466–2473. doi: 10.1128/jb.174.8.2466-2473.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Doig P., Austin J. W., Trust T. J. The Helicobacter pylori 19.6-kilodalton protein is an iron-containing protein resembling ferritin. J Bacteriol. 1993 Jan;175(2):557–560. doi: 10.1128/jb.175.2.557-560.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dunn B. E., Campbell G. P., Perez-Perez G. I., Blaser M. J. Purification and characterization of urease from Helicobacter pylori. J Biol Chem. 1990 Jun 5;265(16):9464–9469. [PubMed] [Google Scholar]
  14. Dunn B. E., Perez-Perez G. I., Blaser M. J. Two-dimensional gel electrophoresis and immunoblotting of Campylobacter pylori proteins. Infect Immun. 1989 Jun;57(6):1825–1833. doi: 10.1128/iai.57.6.1825-1833.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dunn B. E., Roop R. M., 2nd, Sung C. C., Sharma S. A., Perez-Perez G. I., Blaser M. J. Identification and purification of a cpn60 heat shock protein homolog from Helicobacter pylori. Infect Immun. 1992 May;60(5):1946–1951. doi: 10.1128/iai.60.5.1946-1951.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dunn B. E., Vakil N. B., Schneider B. G., Miller M. M., Zitzer J. B., Peutz T., Phadnis S. H. Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies. Infect Immun. 1997 Apr;65(4):1181–1188. doi: 10.1128/iai.65.4.1181-1188.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Eaton K. A., Brooks C. L., Morgan D. R., Krakowka S. Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets. Infect Immun. 1991 Jul;59(7):2470–2475. doi: 10.1128/iai.59.7.2470-2475.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Eaton K. A., Krakowka S. Avirulent, urease-deficient Helicobacter pylori colonizes gastric epithelial explants ex vivo. Scand J Gastroenterol. 1995 May;30(5):434–437. doi: 10.3109/00365529509093303. [DOI] [PubMed] [Google Scholar]
  19. Eaton K. A., Krakowka S. Effect of gastric pH on urease-dependent colonization of gnotobiotic piglets by Helicobacter pylori. Infect Immun. 1994 Sep;62(9):3604–3607. doi: 10.1128/iai.62.9.3604-3607.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Eschweiler B., Bohrmann B., Gerstenecker B., Schiltz E., Kist M. In situ localization of the 60 k protein of Helicobacter pylori, which belongs to the family of heat shock proteins, by immuno-electron microscopy. Zentralbl Bakteriol. 1993 Sep;280(1-2):73–85. doi: 10.1016/s0934-8840(11)80942-4. [DOI] [PubMed] [Google Scholar]
  21. Evans D. J., Jr, Evans D. G., Kirkpatrick S. S., Graham D. Y. Characterization of the Helicobacter pylori urease and purification of its subunits. Microb Pathog. 1991 Jan;10(1):15–26. doi: 10.1016/0882-4010(91)90062-f. [DOI] [PubMed] [Google Scholar]
  22. Fath M. J., Kolter R. ABC transporters: bacterial exporters. Microbiol Rev. 1993 Dec;57(4):995–1017. doi: 10.1128/mr.57.4.995-1017.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ferrero R. L., Thiberge J. M., Huerre M., Labigne A. Recombinant antigens prepared from the urease subunits of Helicobacter spp.: evidence of protection in a mouse model of gastric infection. Infect Immun. 1994 Nov;62(11):4981–4989. doi: 10.1128/iai.62.11.4981-4989.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gorden J., Small P. L. Acid resistance in enteric bacteria. Infect Immun. 1993 Jan;61(1):364–367. doi: 10.1128/iai.61.1.364-367.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harris P. R., Mobley H. L., Perez-Perez G. I., Blaser M. J., Smith P. D. Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production. Gastroenterology. 1996 Aug;111(2):419–425. doi: 10.1053/gast.1996.v111.pm8690207. [DOI] [PubMed] [Google Scholar]
  26. Hawtin P. R., Stacey A. R., Newell D. G. Investigation of the structure and localization of the urease of Helicobacter pylori using monoclonal antibodies. J Gen Microbiol. 1990 Oct;136(10):1995–2000. doi: 10.1099/00221287-136-10-1995. [DOI] [PubMed] [Google Scholar]
  27. Hu L. T., Mobley H. L. Expression of catalytically active recombinant Helicobacter pylori urease at wild-type levels in Escherichia coli. Infect Immun. 1993 Jun;61(6):2563–2569. doi: 10.1128/iai.61.6.2563-2569.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hu L. T., Mobley H. L. Purification and N-terminal analysis of urease from Helicobacter pylori. Infect Immun. 1990 Apr;58(4):992–998. doi: 10.1128/iai.58.4.992-998.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jarvis K. G., Girón J. A., Jerse A. E., McDaniel T. K., Donnenberg M. S., Kaper J. B. Enteropathogenic Escherichia coli contains a putative type III secretion system necessary for the export of proteins involved in attaching and effacing lesion formation. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7996–8000. doi: 10.1073/pnas.92.17.7996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jones B. D., Mobley H. L. Proteus mirabilis urease: nucleotide sequence determination and comparison with jack bean urease. J Bacteriol. 1989 Dec;171(12):6414–6422. doi: 10.1128/jb.171.12.6414-6422.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Konishi H., Ishibashi M., Morshed M. G., Nakazawa T. Cytopathic effects of Helicobacter pylori on cultured mammalian cells. J Med Microbiol. 1992 Aug;37(2):118–122. doi: 10.1099/00222615-37-2-118. [DOI] [PubMed] [Google Scholar]
  32. Kreiss C., Buclin T., Cosma M., Corthésy-Theulaz I., Michetti P. Safety of oral immunisation with recombinant urease in patients with Helicobacter pylori infection. Lancet. 1996 Jun 8;347(9015):1630–1631. doi: 10.1016/s0140-6736(96)91119-8. [DOI] [PubMed] [Google Scholar]
  33. Krishnamurthy P., Parlow M., Zitzer J. B., Vakil N. B., Mobley H. L., Levy M., Phadnis S. H., Dunn B. E. Helicobacter pylori containing only cytoplasmic urease is susceptible to acid. Infect Immun. 1998 Nov;66(11):5060–5066. doi: 10.1128/iai.66.11.5060-5066.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lee A., Buck F. Vaccination and mucosal responses to Helicobacter pylori infection. Aliment Pharmacol Ther. 1996 Apr;10 (Suppl 1):129–138. doi: 10.1046/j.1365-2036.1996.22164013.x. [DOI] [PubMed] [Google Scholar]
  35. Lee C. K., Weltzin R., Thomas W. D., Jr, Kleanthous H., Ermak T. H., Soman G., Hill J. E., Ackerman S. K., Monath T. P. Oral immunization with recombinant Helicobacter pylori urease induces secretory IgA antibodies and protects mice from challenge with Helicobacter felis. J Infect Dis. 1995 Jul;172(1):161–172. doi: 10.1093/infdis/172.1.161. [DOI] [PubMed] [Google Scholar]
  36. Mai U. E., Perez-Perez G. I., Allen J. B., Wahl S. M., Blaser M. J., Smith P. D. Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa. J Exp Med. 1992 Feb 1;175(2):517–525. doi: 10.1084/jem.175.2.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mai U. E., Perez-Perez G. I., Wahl L. M., Wahl S. M., Blaser M. J., Smith P. D. Soluble surface proteins from Helicobacter pylori activate monocytes/macrophages by lipopolysaccharide-independent mechanism. J Clin Invest. 1991 Mar;87(3):894–900. doi: 10.1172/JCI115095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Marshall B. J., Barrett L. J., Prakash C., McCallum R. W., Guerrant R. L. Urea protects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid. Gastroenterology. 1990 Sep;99(3):697–702. doi: 10.1016/0016-5085(90)90957-3. [DOI] [PubMed] [Google Scholar]
  39. McColm A. A., Bagshaw J. A., O'Malley C. F. Development of a 14C-urea breath test in ferrets colonised with Helicobacter mustelae: effects of treatment with bismuth, antibiotics, and urease inhibitors. Gut. 1993 Feb;34(2):181–186. doi: 10.1136/gut.34.2.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. McGowan C. C., Cover T. L., Blaser M. J. The proton pump inhibitor omeprazole inhibits acid survival of Helicobacter pylori by a urease-independent mechanism. Gastroenterology. 1994 Nov;107(5):1573–1578. doi: 10.1016/0016-5085(94)90582-7. [DOI] [PubMed] [Google Scholar]
  41. Michetti P., Corthésy-Theulaz I., Davin C., Haas R., Vaney A. C., Heitz M., Bille J., Kraehenbuhl J. P., Saraga E., Blum A. L. Immunization of BALB/c mice against Helicobacter felis infection with Helicobacter pylori urease. Gastroenterology. 1994 Oct;107(4):1002–1011. doi: 10.1016/0016-5085(94)90224-0. [DOI] [PubMed] [Google Scholar]
  42. Mobley H. L., Garner R. M., Bauerfeind P. Helicobacter pylori nickel-transport gene nixA: synthesis of catalytically active urease in Escherichia coli independent of growth conditions. Mol Microbiol. 1995 Apr;16(1):97–109. doi: 10.1111/j.1365-2958.1995.tb02395.x. [DOI] [PubMed] [Google Scholar]
  43. Mobley H. L., Island M. D., Hausinger R. P. Molecular biology of microbial ureases. Microbiol Rev. 1995 Sep;59(3):451–480. doi: 10.1128/mr.59.3.451-480.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Mobley H. L. The role of Helicobacter pylori urease in the pathogenesis of gastritis and peptic ulceration. Aliment Pharmacol Ther. 1996 Apr;10 (Suppl 1):57–64. doi: 10.1046/j.1365-2036.1996.22164006.x. [DOI] [PubMed] [Google Scholar]
  45. Mégraud F., Neman-Simha V., Brügmann D. Further evidence of the toxic effect of ammonia produced by Helicobacter pylori urease on human epithelial cells. Infect Immun. 1992 May;60(5):1858–1863. doi: 10.1128/iai.60.5.1858-1863.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Nielsen H., Andersen L. P. Activation of human phagocyte oxidative metabolism by Helicobacter pylori. Gastroenterology. 1992 Dec;103(6):1747–1753. doi: 10.1016/0016-5085(92)91430-c. [DOI] [PubMed] [Google Scholar]
  47. Nomura A., Stemmermann G. N., Chyou P. H., Kato I., Perez-Perez G. I., Blaser M. J. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991 Oct 17;325(16):1132–1136. doi: 10.1056/NEJM199110173251604. [DOI] [PubMed] [Google Scholar]
  48. O'Toole P. W., Janzon L., Doig P., Huang J., Kostrzynska M., Trust T. J. The putative neuraminyllactose-binding hemagglutinin HpaA of Helicobacter pylori CCUG 17874 is a lipoprotein. J Bacteriol. 1995 Nov;177(21):6049–6057. doi: 10.1128/jb.177.21.6049-6057.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. O'Toole P. W., Logan S. M., Kostrzynska M., Wadström T., Trust T. J. Isolation and biochemical and molecular analyses of a species-specific protein antigen from the gastric pathogen Helicobacter pylori. J Bacteriol. 1991 Jan;173(2):505–513. doi: 10.1128/jb.173.2.505-513.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Odenbreit S., Wieland B., Haas R. Cloning and genetic characterization of Helicobacter pylori catalase and construction of a catalase-deficient mutant strain. J Bacteriol. 1996 Dec;178(23):6960–6967. doi: 10.1128/jb.178.23.6960-6967.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Park I. S., Hausinger R. P. Site-directed mutagenesis of Klebsiella aerogenes urease: identification of histidine residues that appear to function in nickel ligation, substrate binding, and catalysis. Protein Sci. 1993 Jun;2(6):1034–1041. doi: 10.1002/pro.5560020616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991 Oct 17;325(16):1127–1131. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
  53. Parsonnet J., Hansen S., Rodriguez L., Gelb A. B., Warnke R. A., Jellum E., Orentreich N., Vogelman J. H., Friedman G. D. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994 May 5;330(18):1267–1271. doi: 10.1056/NEJM199405053301803. [DOI] [PubMed] [Google Scholar]
  54. Phadnis S. H., Parlow M. H., Levy M., Ilver D., Caulkins C. M., Connors J. B., Dunn B. E. Surface localization of Helicobacter pylori urease and a heat shock protein homolog requires bacterial autolysis. Infect Immun. 1996 Mar;64(3):905–912. doi: 10.1128/iai.64.3.905-912.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Pugsley A. P. The complete general secretory pathway in gram-negative bacteria. Microbiol Rev. 1993 Mar;57(1):50–108. doi: 10.1128/mr.57.1.50-108.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Pérez-Pérez G. I., Gower C. B., Blaser M. J. Effects of cations on Helicobacter pylori urease activity, release, and stability. Infect Immun. 1994 Jan;62(1):299–302. doi: 10.1128/iai.62.1.299-302.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Smoot D. T., Mobley H. L., Chippendale G. R., Lewison J. F., Resau J. H. Helicobacter pylori urease activity is toxic to human gastric epithelial cells. Infect Immun. 1990 Jun;58(6):1992–1994. doi: 10.1128/iai.58.6.1992-1994.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Spiegelhalder C., Gerstenecker B., Kersten A., Schiltz E., Kist M. Purification of Helicobacter pylori superoxide dismutase and cloning and sequencing of the gene. Infect Immun. 1993 Dec;61(12):5315–5325. doi: 10.1128/iai.61.12.5315-5325.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Sriwanthana B., Mobley H. L. Proteus mirabilis urease: histidine 320 of UreC is essential for urea hydrolysis and nickel ion binding within the native enzyme. Infect Immun. 1993 Jun;61(6):2570–2577. doi: 10.1128/iai.61.6.2570-2577.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Stadtländer C. T., Gangemi J. D., Khanolkar S. S., Kitsos C. M., Farris H. E., Jr, Fulton L. K., Hill J. E., Huntington F. K., Lee C. K., Monath T. P. Immunogenicity and safety of recombinant Helicobacter pylori urease in a nonhuman primate. Dig Dis Sci. 1996 Sep;41(9):1853–1862. doi: 10.1007/BF02088757. [DOI] [PubMed] [Google Scholar]
  61. Suerbaum S., Thiberge J. M., Kansau I., Ferrero R. L., Labigne A. Helicobacter pylori hspA-hspB heat-shock gene cluster: nucleotide sequence, expression, putative function and immunogenicity. Mol Microbiol. 1994 Dec;14(5):959–974. doi: 10.1111/j.1365-2958.1994.tb01331.x. [DOI] [PubMed] [Google Scholar]
  62. Talley N. J., Ormand J. E., Frie C. A., Zinsmeister A. R. Stability of pH gradients in vivo across the stomach in Helicobacter pylori gastritis, dyspepsia, and health. Am J Gastroenterol. 1992 May;87(5):590–594. [PubMed] [Google Scholar]
  63. Tsuda M., Karita M., Morshed M. G., Okita K., Nakazawa T. A urease-negative mutant of Helicobacter pylori constructed by allelic exchange mutagenesis lacks the ability to colonize the nude mouse stomach. Infect Immun. 1994 Aug;62(8):3586–3589. doi: 10.1128/iai.62.8.3586-3589.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983 Jun 4;1(8336):1273–1275. [PubMed] [Google Scholar]

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