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Gene Review

TEM-1  -  hypothetical protein

Escherichia coli

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Disease relevance of TEM-1

  • The conserved Class A beta-lactamase active site residue Tyr-105 was substituted by saturation mutagenesis in TEM-1 beta-lactamase from Escherichia coli in order to clarify its role in enzyme activity and in substrate stabilization and discrimination [1].
  • BLIP-I inhibited Bacto(R) Penase (Difco), and plasmid encoded TEM-1 beta-lactamase, whereas it did not inhibit Enterobacter cloacae beta-lactamases [2].
  • The beta-lactamase inhibitor protein (BLIP) of Streptomyces clavuligerus, is a potent inhibitor of several beta-lactamases, including the TEM-1 enzyme (Ki = 0.6 nM) [3].
  • Phage display was used to determine which residues within the turn regions of BLIP are critical for binding TEM-1 beta-lactamase [4].
  • While investigating the genetic basis of biofilm development by Pseudomonas aeruginosa, we noted that plasmid vectors encoding the common beta-lactamase marker TEM-1 caused defects in twitching motility (mediated by type IV pili), adherence and biofilm formation without affecting growth rates [5].

High impact information on TEM-1

  • TEM-1 plasmids in the community [6].
  • We demonstrate this approach by recombining the genes coding for TEM1 beta-lactamase (BLA) and the Escherichia coli maltose binding protein (MBP) to create a family of MBP-BLA hybrids in which maltose is a positive or negative effector of beta-lactam hydrolysis [7].
  • We demonstrate that our error-prone Pol I can be used to generate enzymes with distinct properties by generating TEM-1 beta-lactamase mutants able to hydrolyze a third-generation lactam antibiotic, aztreonam [8].
  • To test this theory, TEM-1 beta-lactamase was evolved using a hypermutator E. coli-based directed evolution technique with cefotaxime selection [9].
  • A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation [10].

Chemical compound and disease context of TEM-1

  • X-ray structure of the Asn276Asp variant of the Escherichia coli TEM-1 beta-lactamase: direct observation of electrostatic modulation in resistance to inactivation by clavulanic acid [11].
  • We performed an investigation of the pH-dependent quenching of the fluorescence of tryptophan residues of TEM-1 beta-lactamase from E. coli by uncharged and charged quenchers. pH-dependent Stern-Volmer constants (Ksv/pH) of tryptophan residues allowed us to determine subtle but discrete structurally and functionally important processes [12].
  • Three independent methods were used in this report to address the question of the protonation state of this important lysine (Lys-73) in the TEM-1 beta-lactamase from Escherichia coli [13].
  • Site-directed mutagenesis at the active site of Escherichia coli TEM-1 beta-lactamase. Suicide inhibitor-resistant mutants reveal the role of arginine 244 and methionine 69 in catalysis [14].
  • These strains included six clinical isolates (MICs from 2/1 micrograms/ml [with 2 and 1 microgram/ml being the respective concentrations of ampicillin and sulbactam] to 32/16 micrograms/ml) with similar degrees of virulence in mice and a laboratory genetic transformant (E. coli AFE) which hyperproduces TEM-1 (MIC = 128/64 micrograms/ml) [15].

Biological context of TEM-1

  • Finally, by performing a short molecular dynamics study on a restricted set of Y105X mutants of TEM-1, we found that the strong aromatic bias observed at position 105 in Class A beta-lactamases is primarily defined by a structural requirement, selecting planar residues that form a stabilizing wall to the active site [1].
  • Site-saturation mutagenesis of Tyr-105 reveals its importance in substrate stabilization and discrimination in TEM-1 beta-lactamase [1].
  • Three of these new enzymes derived from TEM-1 by only one amino acid substitution (Ser130Gly, Arg244Gly, and Asn276Asp), whereas three others derived by two amino acid substitutions (Met69Leu and Arg244Ser, Met69Leu and Ile127Val, and Met69Val and Arg275Gln) [16].
  • The amino acid sequence of TEM-5, which confers higher levels of resistance to Caz than to other recently developed cephalosporins, differed from that of TEM-1 by three mutations distinct from those of TEM-4 [17].
  • The susceptibility to mecillinam indicated that this phenotype was not related to hyperproduction of the TEM-1 beta-lactamase [18].

Anatomical context of TEM-1


Associations of TEM-1 with chemical compounds

  • The carboxylate of Asp 49 forms hydrogen bonds to four conserved, catalytic residues in the beta-lactamase, thereby mimicking the position of the penicillin G carboxylate observed in the acyl-enzyme complex of TEM-1 with substrate [23].
  • In this study, we have characterized the kinetic properties of the inhibition process of the wild-type TEM-1 beta-lactamase and of its Asn276Asp variant with the three clinically used inactivators, clavulanic acid (clavulanate), sulbactam, and tazobactam, and we report the X-ray structure for the mutant variant at 2.3 A resolution [11].
  • The TEM-4 enzyme, which confers high-level resistance to cefotaxime (Ctx) and ceftazidime (Caz), differed from the TEM-1 penicillinase by four amino acid substitutions [17].
  • Analysis of the location of the mutations in the primary and tertiary structures of class A beta-lactamases suggests that interactions between the substituted residues and beta-lactam antibiotics non-hydrolysable by TEM-1 and TEM-2 allow TEM-4 and TEM-5 to hydrolyse efficiently novel broad-spectrum cephalosporins such as Ctx and Caz [17].
  • The determination of the amino acid sequence (Swiss-Prot accession number, P00810) of the purified protein indicated that IRT-4 differed from TEM-1 by two substitutions: Leu for Met-69 (ABL numbering) and Asp for Asn-276 [18].

Other interactions of TEM-1

  • Isolates producing either AmpC or OXA-1 enzymes or producing high levels of TEM-1 beta-lactamases had susceptibility patterns that were difficult to distinguish without IEF and/or amplification of the corresponding specific genes [24].
  • The latter was determined by use of a pair of reporter plasmids carrying supercoiling-dependent promoters pgyrA and ptopA, respectively, transcriptionally fused to the reporter gene bla coding for TEM-1 beta-lactamase [25].
  • All but 1 of the 33 E. coli phenotypes found to be TEM-1 positive were uniformly positive for the beta-lactamase gene, whereas some of the phenotypes found to be positive for OXA-1 (2 of 3) and SHV-1 (6 of 70) were occasionally negative for the respective genes [26].
  • CTX-M-15, OXA-30 and TEM-1-producing Escherichia coli in two Portuguese regions [27].
  • These nine antimicrobial resistance mechanisms comprised two extended-spectrum beta-lactamases (ESBLs) (PER-2 and CTX-M-2), TEM-1-like, OXA-9-like, AAC(3)-IIa, AAC(6')-Ib, ANT(3")-Ia and resistance determinants to tetracycline and chloramphenicol [28].

Analytical, diagnostic and therapeutic context of TEM-1

  • Fourteen of these isolates produced TEM-1 beta-lactamase alone, and the other six showed an additional band at pI 9.0-9.2 on IEF and the ampC gene by PCR, indicating the simultaneous production of AmpC enzyme [24].
  • A Met-69-Leu variant of TEM-1, obtained by site-directed mutagenesis, has been described as resistant to clavulanate [18].
  • We report here that selected mutants had a minimum inhibitory concentration of 640 micrograms ml-1, a 32,000-fold increase and 64-fold greater than any published TEM-1 derived enzyme [29].
  • Isoelectric focusing studies demonstrated three beta-lactamases, with pIs of 7.2 (SHV-29), 6.7 (KPC-1), and 5.4 (TEM-1) [30].
  • PCR screening and sequence analysis of the PCR products for bla(TEM), bla(SHV), and bla(CTX-M) identified TEM-1 in 11 isolates, SHV-12 in 7 isolates, SHV-1 in 1 isolate, a CTX-M-2-like gene in 2 isolates, and CTX-M-26 in 1 isolate [31].


  1. Site-saturation mutagenesis of Tyr-105 reveals its importance in substrate stabilization and discrimination in TEM-1 beta-lactamase. Doucet, N., De Wals, P.Y., Pelletier, J.N. J. Biol. Chem. (2004) [Pubmed]
  2. New beta -lactamase inhibitory protein (BLIP-I) from Streptomyces exfoliatus SMF19 and its roles on the morphological differentiation. Kang, S.G., Park, H.U., Lee, H.S., Kim, H.T., Lee, K.J. J. Biol. Chem. (2000) [Pubmed]
  3. Contributions of aspartate 49 and phenylalanine 142 residues of a tight binding inhibitory protein of beta-lactamases. Petrosino, J., Rudgers, G., Gilbert, H., Palzkill, T. J. Biol. Chem. (1999) [Pubmed]
  4. Design of potent beta-lactamase inhibitors by phage display of beta-lactamase inhibitory protein. Huang, W., Zhang, Z., Palzkill, T. J. Biol. Chem. (2000) [Pubmed]
  5. Common beta-lactamases inhibit bacterial biofilm formation. Gallant, C.V., Daniels, C., Leung, J.M., Ghosh, A.S., Young, K.D., Kotra, L.P., Burrows, L.L. Mol. Microbiol. (2005) [Pubmed]
  6. TEM-1 plasmids in the community. Thomson, C.J., Shanahan, P.M., Amyes, S.G. Lancet (1994) [Pubmed]
  7. Directed evolution of protein switches and their application to the creation of ligand-binding proteins. Guntas, G., Mansell, T.J., Kim, J.R., Ostermeier, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Targeted gene evolution in Escherichia coli using a highly error-prone DNA polymerase I. Camps, M., Naukkarinen, J., Johnson, B.P., Loeb, L.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  9. Predicting the emergence of antibiotic resistance by directed evolution and structural analysis. Orencia, M.C., Yoon, J.S., Ness, J.E., Stemmer, W.P., Stevens, R.C. Nat. Struct. Biol. (2001) [Pubmed]
  10. A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation. Sideraki, V., Huang, W., Palzkill, T., Gilbert, H.F. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  11. X-ray structure of the Asn276Asp variant of the Escherichia coli TEM-1 beta-lactamase: direct observation of electrostatic modulation in resistance to inactivation by clavulanic acid. Swarén, P., Golemi, D., Cabantous, S., Bulychev, A., Maveyraud, L., Mobashery, S., Samama, J.P. Biochemistry (1999) [Pubmed]
  12. pH-dependent quenching of the fluorescence of tryptophan residues in class A beta-lactamase from E. coli (TEM-1). Christov, C., Ianev, D., Shosheva, A., Atanasov, B. Z. Naturforsch., C, J. Biosci. (2004) [Pubmed]
  13. The importance of a critical protonation state and the fate of the catalytic steps in class A beta-lactamases and penicillin-binding proteins. Golemi-Kotra, D., Meroueh, S.O., Kim, C., Vakulenko, S.B., Bulychev, A., Stemmler, A.J., Stemmler, T.L., Mobashery, S. J. Biol. Chem. (2004) [Pubmed]
  14. Site-directed mutagenesis at the active site of Escherichia coli TEM-1 beta-lactamase. Suicide inhibitor-resistant mutants reveal the role of arginine 244 and methionine 69 in catalysis. Delaire, M., Labia, R., Samama, J.P., Masson, J.M. J. Biol. Chem. (1992) [Pubmed]
  15. Comparison of ampicillin-sulbactam regimens simulating 1.5- and 3.0-gram doses to humans in treatment of Escherichia coli bacteremia in mice. Lister, P.D., Sanders, C.C. Antimicrob. Agents Chemother. (1995) [Pubmed]
  16. Epidemiological survey of amoxicillin-clavulanate resistance and corresponding molecular mechanisms in Escherichia coli isolates in France: new genetic features of bla(TEM) genes. Leflon-Guibout, V., Speldooren, V., Heym, B., Nicolas-Chanoine, M. Antimicrob. Agents Chemother. (2000) [Pubmed]
  17. Characterization of the plasmid genes blaT-4 and blaT-5 which encode the broad-spectrum beta-lactamases TEM-4 and TEM-5 in enterobacteriaceae. Sougakoff, W., Petit, A., Goussard, S., Sirot, D., Bure, A., Courvalin, P. Gene (1989) [Pubmed]
  18. Characterization and amino acid sequence of IRT-4, a novel TEM-type enzyme with a decreased susceptibility to beta-lactamase inhibitors. Brun, T., Péduzzi, J., Caniça, M.M., Paul, G., Névot, P., Barthélémy, M., Labia, R. FEMS Microbiol. Lett. (1994) [Pubmed]
  19. DNA vaccination for the priming of neutralizing antibodies against non-immunogenic STa enterotoxin from enterotoxigenic Escherichia coli. Ruth, N., Mainil, J., Roupie, V., Frère, J.M., Galleni, M., Huygen, K. Vaccine (2005) [Pubmed]
  20. Bactericidal activity of oral beta-lactam antibiotics in plasma and urine versus isogenic Escherichia coli strains producing broad- and extended-spectrum beta-lactamases. Bedenic, B., Vranes, J., Suto, S., Zagar, Z. Int. J. Antimicrob. Agents (2005) [Pubmed]
  21. Different mechanisms of TEM-1 and Oxa-1 mediated resistance to piperacillin in E. coli. Marre, R., Borner, K., Schulz, E. Zentralblatt für Bakteriologie, Mikrobiologie, und Hygiene. Series A, Medical microbiology, infectious diseases, virology, parasitology. (1984) [Pubmed]
  22. Competition between DsbA-mediated oxidation and conformational folding of RTEM1 beta-lactamase. Frech, C., Wunderlich, M., Glockshuber, R., Schmid, F.X. Biochemistry (1996) [Pubmed]
  23. A potent new mode of beta-lactamase inhibition revealed by the 1.7 A X-ray crystallographic structure of the TEM-1-BLIP complex. Strynadka, N.C., Jensen, S.E., Alzari, P.M., James, M.N. Nat. Struct. Biol. (1996) [Pubmed]
  24. Patterns and mechanisms of resistance to beta-lactams and beta-lactamase inhibitors in uropathogenic Escherichia coli isolated from dogs in Portugal. Féria, C., Ferreira, E., Correia, J.D., Gonçalves, J., Caniça, M. J. Antimicrob. Chemother. (2002) [Pubmed]
  25. Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli. Bagel, S., Hüllen, V., Wiedemann, B., Heisig, P. Antimicrob. Agents Chemother. (1999) [Pubmed]
  26. Epidemiology of plasmid-mediated beta-lactamases in enterobacteria Swedish neonatal wards and relation to antimicrobial therapy. Burman, L.G., Haeggman, S., Kuistila, M., Tullus, K., Huovinen, P. Antimicrob. Agents Chemother. (1992) [Pubmed]
  27. CTX-M-15, OXA-30 and TEM-1-producing Escherichia coli in two Portuguese regions. Mendonça, N., Louro, D., Castro, A.P., Diogo, J., Caniça, M. J. Antimicrob. Chemother. (2006) [Pubmed]
  28. Multiple antibiotic-resistance mechanisms including a novel combination of extended-spectrum beta-lactamases in a Klebsiella pneumoniae clinical strain isolated in Argentina. Melano, R., Corso, A., Petroni, A., Centrón, D., Orman, B., Pereyra, A., Moreno, N., Galas, M. J. Antimicrob. Chemother. (2003) [Pubmed]
  29. Rapid evolution of a protein in vitro by DNA shuffling. Stemmer, W.P. Nature (1994) [Pubmed]
  30. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Yigit, H., Queenan, A.M., Anderson, G.J., Domenech-Sanchez, A., Biddle, J.W., Steward, C.D., Alberti, S., Bush, K., Tenover, F.C. Antimicrob. Agents Chemother. (2001) [Pubmed]
  31. Extended-spectrum beta-lactamases among Enterobacter isolates obtained in Tel Aviv, Israel. Schlesinger, J., Navon-Venezia, S., Chmelnitsky, I., Hammer-Münz, O., Leavitt, A., Gold, H.S., Schwaber, M.J., Carmeli, Y. Antimicrob. Agents Chemother. (2005) [Pubmed]
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