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Gene Review

mrdA  -  penicillin-binding protein 2

Escherichia coli CFT073

 
 
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Disease relevance of mrdA

 

High impact information on mrdA

  • Mecillinam, a beta-lactam antibiotic which specifically inactivates penicillin binding protein 2 (PBP2) in Escherichia coli, prevents lateral cell wall elongation, inducing spherical morphology and cell death [1].
  • It possesses active PBP2, as evidenced by its rod shape in the absence of mecillinam (but not in its presence), its ability to filament when septation is inhibited, and its penicillin-binding ability [6].
  • Mecillinam, a beta-lactam antibiotic which binds specifically to penicillin-binding protein 2 (PBP2), blocks lateral cell-wall elongation, induces spherical morphology and ultimately kills bacteria [6].
  • (A) Cell shape: beta-Lactams that specifically result in the production of ovoid cells bind to penicillin binding protein 2 (molecular weight 66,000) [7].
  • We have previously shown that PBP2 inactivation results in a cell division block and that an increased concentration of the nucleotide ppGpp, effector of the RelA-dependent stringent response, confers mecillinam resistance and allows cells to divide as spheres in the absence of PBP2 activity [8].
 

Chemical compound and disease context of mrdA

 

Biological context of mrdA

  • Division in the absence of PBP2 activity is restored (and resistance to mecillinam is conferred) when the three cell division proteins FtsQ, FtsA and FtsZ are overproduced, but not when only one or two of them are overproduced [11].
  • By means of amino acid sequence alignment with class A beta-lactamases, the residues essential for the catalytic activity of the peptidoglycan transpeptidase of penicillin-binding protein 2 (PBP2) have been predicted to be Lys333, Asp447, and Lys544, in addition to the acylation site residue for the acyl-enzyme mechanism, Ser330 [12].
  • Active-site residues of the transpeptidase domain of penicillin-binding protein 2 from Escherichia coli: similarity in catalytic mechanism to class A beta-lactamases [12].
  • On the other hand, the simultaneous absence of PBP-2 and inhibition of PBP-3 causes a significant reduction of peptidoglycan synthesis, yet only slightly affected cell viability [13].
  • Nucleotide sequence of the pbpA gene and characteristics of the deduced amino acid sequence of penicillin-binding protein 2 of Escherichia coli K12 [14].
 

Anatomical context of mrdA

  • When the recombinant PBP 2 molecules were overexpressed in Escherichia coli, insoluble PBP 2 inclusion bodies, which could be isolated by low-speed centrifugation of cell lysates, were formed [15].
  • The affinity of soluble PBP 2' for [3H]penicillin G was decreased fourfold relative to that of soluble PBP 2, and their affinities were found to be identical to the affinities of the full-length PBP 2 enzymes that were previously determined in N. gonorrhoeae membranes [15].
 

Associations of mrdA with chemical compounds

  • EGCg showed a synergistic effect with DL-cycloserine (an inhibitor of cell wall synthesis unrelated to PBP2') but additive or indifferent effect with inhibitors of protein and nuclear acid synthesis [16].
  • Surprisingly, it has been reported that beta-lactamase is not induced by cefoxitin in the absence of FtsZ, which is required for cell division, or in the absence of penicillin-binding protein 2 (PBP2), which is required for cell elongation [17].
  • In a cya mutant lacking PBP2, the restoration of a Cya+ phenotype by addition of cyclic AMP caused lethality and a block in cell division [18].
  • The reduction in the affinity of PBP 2 is largely due to the insertion of an aspartic acid residue (Asp-345a) into the amino acid sequence of PBP 2 [15].
  • Addition of nalidixic acid (20 micrograms/ml) at the temperature shift from 30 to 42 degrees C resulted in lysis of some cells and appearance of spheroidal bulges along the cylinders in other cells, consistent with the hypothesis of envelope weakening due to inactivation of PBP-2 [19].
 

Analytical, diagnostic and therapeutic context of mrdA

  • The pattern of peptidoglycan (murein) segregation in cells of Escherichia coli with impaired activity of the morphogenetic proteins penicillin-binding protein 2 and RodA has been investigated by the D-cysteine-biotin immunolabeling technique (M. A. de Pedro, J. C. Quintela, J.-V. Höltje, and H. Schwarz, J. Bacteriol. 179:2823-2834, 1997) [20].
  • After renaturation, gel filtration was used to separate monomeric soluble PBP 2 from improperly folded protein aggregates and other protein contaminants [15].

References

  1. Penicillin binding protein 2 is dispensable in Escherichia coli when ppGpp synthesis is induced. Vinella, D., D'Ari, R., Jaffé, A., Bouloc, P. EMBO J. (1992) [Pubmed]
  2. MreB, the cell shape-determining bacterial actin homologue, co-ordinates cell wall morphogenesis in Caulobacter crescentus. Figge, R.M., Divakaruni, A.V., Gober, J.W. Mol. Microbiol. (2004) [Pubmed]
  3. The Enterococcus hirae R40 penicillin-binding protein 5 and the methicillin-resistant Staphylococcus aureus penicillin-binding protein 2' are similar. el Kharroubi, A., Jacques, P., Piras, G., Van Beeumen, J., Coyette, J., Ghuysen, J.M. Biochem. J. (1991) [Pubmed]
  4. Synergic post-antibiotic effect of mecillinam, in combination with other beta-lactam antibiotics in relation to morphology and initial killing. Hanberger, H., Nilsson, L.E., Svensson, E., Maller, R. J. Antimicrob. Chemother. (1991) [Pubmed]
  5. Molecular cloning and characterization of the genes (pbpA and rodA) responsible for the rod shape of Escherichia coli K-12: analysis of gene expression with transposon Tn5 mutagenesis and protein synthesis directed by constructed plasmids. Asoh, S., Matsuzawa, H., Matsuhashi, M., Ohta, T. J. Bacteriol. (1983) [Pubmed]
  6. The Escherichia coli lov gene product connects peptidoglycan synthesis, ribosomes and growth rate. Bouloc, P., Jaffé, A., D'Ari, R. EMBO J. (1989) [Pubmed]
  7. Distinct penicillin binding proteins involved in the division, elongation, and shape of Escherichia coli K12. Spratt, B.G. Proc. Natl. Acad. Sci. U.S.A. (1975) [Pubmed]
  8. Iron limitation induces SpoT-dependent accumulation of ppGpp in Escherichia coli. Vinella, D., Albrecht, C., Cashel, M., D'Ari, R. Mol. Microbiol. (2005) [Pubmed]
  9. Purification of penicillin-binding protein 2 of Escherichia coli. Curtis, S.J., Strominger, J.L. J. Bacteriol. (1981) [Pubmed]
  10. Novel S-benzylisothiourea compound that induces spherical cells in Escherichia coli probably by acting on a rod-shape-determining protein(s) other than penicillin-binding protein 2. Iwai, N., Nagai, K., Wachi, M. Biosci. Biotechnol. Biochem. (2002) [Pubmed]
  11. Analysis of the effect of ppGpp on the ftsQAZ operon in Escherichia coli. Navarro, F., Robin, A., D'Ari, R., Joseleau-Petit, D. Mol. Microbiol. (1998) [Pubmed]
  12. Active-site residues of the transpeptidase domain of penicillin-binding protein 2 from Escherichia coli: similarity in catalytic mechanism to class A beta-lactamases. Adachi, H., Ishiguro, M., Imajoh, S., Ohta, T., Matsuzawa, H. Biochemistry (1992) [Pubmed]
  13. Murein synthesis and beta-lactam antibiotic susceptibility during rod-to-sphere transition in a pbpA(Ts) mutant of Escherichia coli. Botta, G.A., Buffa, D. Antimicrob. Agents Chemother. (1981) [Pubmed]
  14. Nucleotide sequence of the pbpA gene and characteristics of the deduced amino acid sequence of penicillin-binding protein 2 of Escherichia coli K12. Asoh, S., Matsuzawa, H., Ishino, F., Strominger, J.L., Matsuhashi, M., Ohta, T. Eur. J. Biochem. (1986) [Pubmed]
  15. Expression and purification of a soluble form of penicillin-binding protein 2 from both penicillin-susceptible and penicillin-resistant Neisseria gonorrhoeae. Schultz, D.E., Spratt, B.G., Nicholas, R.A. Protein Expr. Purif. (1991) [Pubmed]
  16. Mechanism of synergy between epigallocatechin gallate and beta-lactams against methicillin-resistant Staphylococcus aureus. Zhao, W.H., Hu, Z.Q., Okubo, S., Hara, Y., Shimamura, T. Antimicrob. Agents Chemother. (2001) [Pubmed]
  17. Role of the murein precursor UDP-N-acetylmuramyl-L-Ala-gamma-D-Glu-meso-diaminopimelic acid-D-Ala-D-Ala in repression of beta-lactamase induction in cell division mutants. Uehara, T., Park, J.T. J. Bacteriol. (2002) [Pubmed]
  18. Penicillin-binding protein 2 is essential in wild-type Escherichia coli but not in lov or cya mutants. Ogura, T., Bouloc, P., Niki, H., D'Ari, R., Hiraga, S., Jaffé, A. J. Bacteriol. (1989) [Pubmed]
  19. Effects of temperature inactivation of penicillin-binding protein 2 on envelope growth in Escherichia coli. Buchnik, D., Woldringh, C.L., Zaritsky, A. Ann. Inst. Pasteur Microbiol. (1987) [Pubmed]
  20. Constitutive septal murein synthesis in Escherichia coli with impaired activity of the morphogenetic proteins RodA and penicillin-binding protein 2. de Pedro, M.A., Donachie, W.D., Höltje, J.V., Schwarz, H. J. Bacteriol. (2001) [Pubmed]
 
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