DNA sequence analysis of bacterial toxic heavy metal resistances

  • Simon Silver
  • Tapan K. Misra
  • Richard A. Laddaga
Section 2 Metal Binding Proteins and Metal Resistance


Bacterial plasmids have genes that confer highly specific resistances to As, Bi, Cd, Cu, Cr, Hg, Pb, Te, Zn, and other toxic heavy metals. For each toxic cation or anion, generally a different resistance system exists, and these systems may be “linked” together on multiple resistance plasmids. For Cd2+, AsO2 , AsO4 3−, Hg2+, and organomercurials, DNA sequence analysis has supplemented direct physiological and biochemical experiments to produce sophisticated understanding. ThecadA ATPase ofS.aureus plasmids is a 727 amino acid membrane ATPase that pumps Cd2+ from the cells as rapidly as it is accumulated. This polypeptide is related by sequence to other cation translocating ATPases, including the membrane K+ ATPases ofEscherichia coli andStreptococcus faecalis, the H+ ATPases of yeast andNeurospora, the Na+/K+ ATPases of vertebrate animals, and the Ca2+ ATPases of rabbit muscle. The conserved residues include the aspartyl residue that is phosphorylated, the lysine involved in ATP binding, and the proline within a membrane translocating region. The arsenate and arsenite translocating ATPase consists of 3 polypeptides (from DNA sequence analysis), including a recognizable ATP binding protein (arsA), an integral membrane protein (arsB gene), and a substrate specificity subunit (arsC gene). Inorganic mercury and organomercurial degradation is carried out by a series of about 6 polypeptides, including 2 soluble intracellular enzymes (organomercurial lyase and mercuric reductase). The latter is related by sequence and function to glutathione reductase and lipoamide dehydrogenase of prokaryotes and eukaryotes. These enzymes are dimeric, FAD-containing, NAD(P)H-dependent oxidoreductases. Other recognizable polypeptides in themer system include a DNA-binding regulatory protein from themerR gene and a Hg2+ transport system consisting of a periplasmic Hg2+-binding protein (merP gene) and a membrane protein (merT gene) in gram negative systems.

Index Entries

Heavy metal resistance bacterial plasmid resistance cadmium resistance in bacteria mercury resistance in bacteria arsenic resistance in bacteria 


  1. 1.
    S. Silver and T. K. Misra,Ann. Rev. Microbiol. 42, 717 (1988).CrossRefGoogle Scholar
  2. 2.
    R. P. Novick, E. Murphy, T. J. Gryczan, E. Baron, and I. Edelman,Plasmid 2, 109 (1979).PubMedCrossRefGoogle Scholar
  3. 3.
    A. A. Weiss, S. Silver, and T. G. Kinscherf,Antimicrob. Agents Chemother. 14, 856 (1978).PubMedGoogle Scholar
  4. 4.
    Z. Tynecka, Z. Gos, and J. Zajac,J. Bacteriol. 147, 313 (1981).PubMedGoogle Scholar
  5. 5.
    G. Nucifora, L. Chu, T. K. Misra, and S. Silver,Proc. Natl. Acad. Sci. USA,86, in press (1989).Google Scholar
  6. 6.
    S. Silver, G. Nucifora, L. Chu, and T. K. Misra,Trends Biochem. Sci.,14, 76 (1989).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Solioz, S. Mathews, and P. Furst,J. Biol. Chem. 262, 7358 (1987).PubMedGoogle Scholar
  8. 8.
    M. O. Walderhaug, D. C. Dosch, and W. Epstein,Ion. Transport in Prokaryotes, B. P. Rosen and S. Silver, ed., Academic, San Diego, 1987, pp. 85–130.Google Scholar
  9. 9.
    C. J. Brandl, N. M. Green, B. Korczak, and D. H. MacLennan,Cell 44, 597 (1986).PubMedCrossRefGoogle Scholar
  10. 10.
    C. M. Chen, T. K. Misra, S. Silver, and B. P. Rosen,J. Biol. Chem. 261, 15030 (1986).PubMedGoogle Scholar
  11. 11.
    B. P. Rosen, U. Weigel, C. Karkaria, and P. Gangola,J. Biol. Chem. 263, 3067 (1988).PubMedGoogle Scholar
  12. 12.
    S. Silver, K. Budd, K. M. Leahy, W. V. Shaw, D. Hammond, R. P. Novick, G. R. Willsky, M. H. Malamy, and H. Rosenberg,J. Bacteriol. 146, 983 (1981).PubMedGoogle Scholar
  13. 13.
    S. Silver and D. Keach,Proc. Natl. Acad. Sci. USA 79, 6114 (1982).PubMedCrossRefGoogle Scholar
  14. 14.
    H. L. T. Mobley and B. P. Rosen,Proc. Natl. Acad. Sci. USA 79, 6119 (1982).PubMedCrossRefGoogle Scholar
  15. 15.
    R. D. Joerger and P. E. Bishop,J. Bacteriol. 170, 1475 (1988).PubMedGoogle Scholar
  16. 16.
    A. O. Summers,Ann. Rev. Microbiol. 40, 607 (1986).CrossRefGoogle Scholar
  17. 17.
    T. J. Foster,CRC Crit. Rev. Microbiol. 15, 117 (1987).CrossRefGoogle Scholar
  18. 18.
    T. K. Misra, N. L. Brown, D. C. Fritzinger, R. D. Pridmore, W. M. Barnes, L. Haberstroh, and S. Silver,Proc. Natl. Acad. Sci. USA 81, 5975 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    T. K. Misra, N. L. Brown, L. Haberstroh, A. Schmidt, D. Goddette, and S. Silver,Gene 34, 253 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    H. G. Griffin, T. J. Foster, S. Silver, and T. K. Misra,Proc. Natl. Acad. Sci. USA 84, 3112 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    G. Nucifora, L. Chu, S. Silver, and T. K. Misra,J. Bacteriol.,171 in press (1988).Google Scholar
  22. 22.
    N. L. Brown, T. K. Misra, J. N. Winnie, A. Schmidt, M. Seiff, and S. Silver,Mol. Gen. Genet. 202, 143 (1986)PubMedCrossRefGoogle Scholar
  23. 23.
    T. O’Halloran and C. Walsh,Science 235, 211 (1987).PubMedCrossRefGoogle Scholar
  24. 24.
    T. J. Foster and N. L. Brown,J. Bacteriol. 163, 1153 (1985).PubMedGoogle Scholar
  25. 25.
    T. O’Halloran,Metal Ions in Biological Systems, vol. 25, H. Sigel, ed., Marcel Dekker, New York, 1989, in press.Google Scholar
  26. 26.
    N. Ni’Bhriain, S. Silver, and T. J. Foster,J. Bacteriol. 155, 690 (1983).PubMedGoogle Scholar
  27. 27.
    W. J. Jackson and A. O. Summers,J. Bacteriol. 151, 962 (1982).PubMedGoogle Scholar
  28. 28.
    C. O. Pabo and R. T. Sauer,Annu. Rev. Biochem. 53, 293 (1984).PubMedCrossRefGoogle Scholar
  29. 29.
    P. A. Lund and N. L. Brown,Gene 52, 207 (1987).PubMedCrossRefGoogle Scholar
  30. 30.
    H. Nakahara, S. Silver, T. Miki, and R. H. Rownd,J. Bacteriol. 140 161 (1979).PubMedGoogle Scholar
  31. 31.
    D.-F. Feng and R. F. Doolittle,J. Mol. Evol. 25, 351 (1987).PubMedCrossRefGoogle Scholar
  32. 32.
    R. A. Laddaga, L. Chu, T. K. Misra, and S. Silver,Proc. Natl. Acad. Sci. USA 84, 5106 (1987).PubMedCrossRefGoogle Scholar
  33. 33.
    C. T. Walsh, M. D. Distefano, M. J. Moore, L. M. Shewchuk, and G. L. Verdine,FASEB J. 2, 124 (1988).PubMedGoogle Scholar
  34. 34.
    M. D. Distefano, K. G. Au, and C. T. Walsh,Biochemistry, in press (1989).Google Scholar
  35. 35.
    R. Thieme, E. F. Pai, R. H. Schirmer, and G. E. Schulz,J. Mol. Biol. 152, 763 (1981).Google Scholar
  36. 36.
    Y. Wang, M. Moore, H. S. Levinson, S. Silver, C. Walsh, and I. Mahler,J. Bacteriol. 171, 83 (1989).PubMedGoogle Scholar
  37. 37.
    T. P. Begley, A. E. Walts, and C. T. Walsh,Biochemistry 25, 7186 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    T. P. Begley, A. E. Walts, and C. T. Walsh,Biochemistry 25, 7192 (1986).PubMedCrossRefGoogle Scholar
  39. 39.
    M. G. Jobling and D. A. Ritchie,Gene 66, 245 (1988).PubMedCrossRefGoogle Scholar
  40. 40.
    M. A. Mellano and D. A. Cooksey,J. Bacteriol. 170, 2879 (1988).PubMedGoogle Scholar
  41. 41.
    D. Rouch, B. T. O. Lee, and J. Camakaris,Metal Ion Homeostasis: Molecular Biology and Chemistry, D. H. Hamer and D. R. Winge, eds., Liss, New York, 1989, pp. 439–446.Google Scholar
  42. 42.
    D. Nies, M. Mergeay, B. Friedric, and H. G. Schlegel,J. Bacteriol. 169, 4865 (1987).PubMedGoogle Scholar
  43. 43.
    D. H. Nies and S. Silver,J. Bacteriol. 171, 896 (1989).PubMedGoogle Scholar
  44. 44.
    H. Ohtake, C. Cervantes, and S. Silver,J. Bacteriol. 169 3853 (1987).PubMedGoogle Scholar

Copyright information

© The Humana Press Inc. 1989

Authors and Affiliations

  • Simon Silver
    • 1
  • Tapan K. Misra
    • 1
  • Richard A. Laddaga
    • 2
  1. 1.University of Illinois College of MedicineChicago
  2. 2.Bowling Green State UniversityBowling Green

Personalised recommendations