Comparative genomics of regulation of heavy metal resistance in Eubacteria

BackgroundHeavy metal resistance (HMR) in Eubacteria is regulated by a variety of systems including transcription factors from the MerR family (COG0789). The HMR systems are characterized by the complex signal structure (strong palindrome within a 19 or 20 bp promoter spacer), and usually consist of transporter and regulator genes. Some HMR regulons also include detoxification systems. The number of sequenced bacterial genomes is constantly increasing and even though HMR resistance regulons of the COG0789 type usually consist of few genes per genome, the computational analysis may contribute to the understanding of the cellular systems of metal detoxification.ResultsWe studied the mercury (MerR), copper (CueR and HmrR), cadmium (CadR), lead (PbrR), and zinc (ZntR) resistance systems and demonstrated that combining protein sequence analysis and analysis of DNA regulatory signals it was possible to distinguish metal-dependent members of COG0789, assign specificity towards particular metals to uncharacterized loci, and find new genes involved in the metal resistance, in particular, multicopper oxidase and copper chaperones, candidate cytochromes from the copper regulon, new cadmium transporters and, possibly, glutathione-S-transferases.ConclusionOur data indicate that the specificity of the COG0789 systems can be determined combining phylogenetic analysis and identification of DNA regulatory sites. Taking into account signal structure, we can adequately identify genes that are activated using the DNA bending-unbending mechanism. In the case of regulon members that do not reside in single loci, analysis of potential regulatory sites could be crucial for the correct annotation and prediction of the specificity.

[1]  D. Persson,et al.  Copper(I) complexes of penicillamine and glutathione. , 1979, Journal of inorganic biochemistry.

[2]  N. Brown,et al.  The MerR family of transcriptional regulators. , 2003, FEMS microbiology reviews.

[3]  C. Walsh,et al.  Homologous metalloregulatory proteins from both gram-positive and gram-negative bacteria control transcription of mercury resistance operons , 1989, Journal of bacteriology.

[4]  N. Brown,et al.  CueR (YbbI) of Escherichia coli is a MerR family regulator controlling expression of the copper exporter CopA , 2001, Molecular microbiology.

[5]  N. Brown,et al.  Cloning and Functional Analysis of thepbr Lead Resistance Determinant of Ralstonia metallidurans CH34 , 2001, Journal of bacteriology.

[6]  R. Brennan,et al.  Crystal structure of the transcription activator BmrR bound to DNA and a drug , 2001, Nature.

[7]  R. Brennan,et al.  Crystal Structure of MtaN, a Global Multidrug Transporter Gene Activator* , 2001, The Journal of Biological Chemistry.

[8]  J. Wu,et al.  The ArsR protein is a trans‐acting regulatory protein , 1991, Molecular microbiology.

[9]  N. Brown,et al.  A Design for Life: Prokaryotic Metal-binding MerR Family Regulators , 2005, Biometals.

[10]  N. Brown,et al.  ZntR is a Zn(II)‐responsive MerR‐like transcriptional regulator of zntA in Escherichia coli , 1999, Molecular microbiology.

[11]  S. Silver,et al.  Nucleotide sequence and expression of the mercurial-resistance operon from Staphylococcus aureus plasmid pI258. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Kulkarni,et al.  MerR cross-links to the alpha, beta, and sigma 70 subunits of RNA polymerase in the preinitiation complex at the merTPCAD promoter. , 1999, Biochemistry.

[13]  S. Silver,et al.  Bacterial silver resistance: molecular biology and uses and misuses of silver compounds. , 2003, FEMS microbiology reviews.

[14]  N. Brown,et al.  bacterial mercury-resistance genes. , 1997, Metal ions in biological systems.

[15]  W. Jackson,et al.  The DNA sequence of the mercury resistance operon of the IncFII plasmid NR1. , 1984, Journal of molecular and applied genetics.

[16]  C. Rensing,et al.  Genes Involved in Copper Homeostasis inEscherichia coli , 2001, Journal of bacteriology.

[17]  T. O’Halloran,et al.  Transcriptional Activation of an Escherichia coliCopper Efflux Regulon by the Chromosomal MerR Homologue, CueR* , 2000, The Journal of Biological Chemistry.

[18]  H. Yang,et al.  Coordinate genetic regulation of glycogen catabolism and biosynthesis in Escherichia coli via the CsrA gene product , 1996, Journal of bacteriology.

[19]  Susan M. Miller,et al.  Bacterial mercury resistance from atoms to ecosystems. , 2003, FEMS microbiology reviews.

[20]  Chuan He,et al.  An exceptionally selective lead(II)-regulatory protein from Ralstonia metallidurans: development of a fluorescent lead(II) probe. , 2005, Angewandte Chemie.

[21]  S. Silver,et al.  Nucleotide sequence of a chromosomal mercury resistance determinant from a Bacillus sp. with broad-spectrum mercury resistance , 1989, Journal of bacteriology.

[22]  A. Summers.  Untwist and shout: a heavy metal-responsive transcriptional regulator , 1992, Journal of bacteriology.

[23]  N. Brown,et al.  The nucleotide sequence of the mercuric resistance operons of plasmid R100 and transposon Tn501: further evidence for mer genes which enhance the activity of the mercuric ion detoxification system , 2004, Molecular and General Genetics MGG.

[24]  C. Rensing,et al.  CueO is a multi-copper oxidase that confers copper tolerance in Escherichia coli. , 2001, Biochemical and biophysical research communications.

[25]  J. Wu,et al.  Metalloregulated expression of the ars operon. , 1993, The Journal of biological chemistry.

[26]  L. M. Saraiva,et al.  Physico-chemical and spectroscopic properties of the monohemic cytochrome C552 from Pseudomonas nautica 617. , 1994, European journal of biochemistry.

[27]  L. Tisa,et al.  Identification of the metalloregulatory element of the plasmid-encoded arsenical resistance operon. , 1990, Nucleic acids research.

[28]  N. Brown,et al.  Molecular genetics and transport analysis of the copper‐resistance determinant (pco) from Escherichia coli plasmid pRJ1004 , 1995, Molecular microbiology.

[29]  M. Dilworth,et al.  ActP controls copper homeostasis in Rhizobium leguminosarum bv. viciae and Sinorhizobium meliloti preventing low pH‐induced copper toxicity , 2002, Molecular microbiology.

[30]  A. Morby,et al.  Characterisation of CadR from Pseudomonas aeruginosa: a Cd(II)-responsive MerR homologue. , 2003, Biochemical and biophysical research communications.

[31]  A. A. Mironov,et al.  Software for analysis of bacterial genomes , 2000, Molecular Biology.

[32]  A. Mondragón,et al.  Molecular Basis of Metal-Ion Selectivity and Zeptomolar Sensitivity by CueR , 2003, Science.

[33]  David P. Giedroc,et al.  Structural Determinants of Metal Selectivity in Prokaryotic Metal-responsive Transcriptional Regulators , 2005, Biometals.

[34]  C. Rensing,et al.  Pb(II)-translocating P-type ATPases* , 1998, The Journal of Biological Chemistry.

[35]  J. Thompson,et al.  The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. , 1997, Nucleic acids research.

[36]  A A Mironov,et al.  [Software for analyzing bacterial genomes]. , 2000, Molekuliarnaia biologiia.

[37]  D. Nies,et al.  Microbial heavy-metal resistance , 1999, Applied Microbiology and Biotechnology.

[38]  A. Summers,et al.  Cell-Free Mercury(II)-Reducing Activity in a Plasmid-Bearing Strain of Escherichia coli , 1974, Journal of bacteriology.

[39]  T. O’Halloran,et al.  DNA Distortion Mechanism for Transcriptional Activation by ZntR, a Zn(II)-responsive MerR Homologue in Escherichia coli * , 1999, The Journal of Biological Chemistry.

[40]  A. Morby,et al.  Zn(II) metabolism in prokaryotes. , 2003, FEMS microbiology reviews.

[41]  C. Rensing,et al.  The zntA gene of Escherichia coli encodes a Zn(II)-translocating P-type ATPase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Seon-Woo Lee,et al.  Chromosomal Locus for Cadmium Resistance in Pseudomonas putida Consisting of a Cadmium-Transporting ATPase and a MerR Family Response Regulator , 2001, Applied and Environmental Microbiology.

[43]  J. Fraser,et al.  A Gene from Aspergillus nidulans with Similarity to URE2 of Saccharomyces cerevisiae Encodes a Glutathione S-Transferase Which Contributes to Heavy Metal and Xenobiotic Resistance , 2002, Applied and Environmental Microbiology.

[44]  M. Scrutton.  The evolution of metalloenzymes, metalloproteins and related materials : Edited by G. J. Leigh Symposium Press; London, 1977 118 pages. £4.00 , 1978 .

[45]  J. Felsenstein.  Evolutionary trees from DNA sequences: A maximum likelihood approach , 2005, Journal of Molecular Evolution.

[46]  B. Moore.  A new screen test and selective medium for the rapid detection of epidemic strains of Staph. aureus. , 1960, Lancet.

[47]  N. Brown,et al.  The Escherichia coli Copper-responsivecopA Promoter Is Activated by Gold* , 2003, The Journal of Biological Chemistry.

[48]  N. Brown,et al.  Copper-inducible transcriptional regulation at two promoters in the Escherichia coli copper resistance determinant pco. , 1997, Microbiology.

[49]  M. R. Binet,et al.  Cd(II), Pb(II) and Zn(II) ions regulate expression of the metal‐transporting P‐type ATPase ZntA in Escherichia coli , 2000, FEBS letters.

[50]  Thomas V. O'Halloran,et al.  The Independent cue and cusSystems Confer Copper Tolerance during Aerobic and Anaerobic Growth inEscherichia coli * , 2001, The Journal of Biological Chemistry.