| Structural highlights
Function
BLAG2_PSEAI Extended-spectrum beta-lactamase (ESBL) which confers resistance to penicillins, as well as first, third and fourth-generation cephalosporins (PubMed:11502535, PubMed:19656947, PubMed:20696873, PubMed:21220532). Has modest carbapenem-hydrolyzing activity (PubMed:11502535, PubMed:19656947, PubMed:25485972). Has cefotaxime-hydrolyzing activity (PubMed:11502535, PubMed:19656947).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Carbapenems are the last resort antibiotics for treatment of life-threatening infections. The GES beta-lactamases are important contributors to carbapenem resistance in clinical bacterial pathogens. A single amino acid difference at position 170 of the GES-1, GES-2, and GES-5 enzymes is responsible for the expansion of their substrate profile to include carbapenem antibiotics. This highlights the increasing need to understand the mechanisms by which the GES beta-lactamases function to aid in development of novel therapeutics. We demonstrate that the catalytic efficiency of the enzymes with carbapenems meropenem, ertapenem, and doripenem progressively increases (100-fold) from GES-1 to -5, mainly due to an increase in the rate of acylation. The data reveal that while acylation is rate limiting for GES-1 and GES-2 for all three carbapenems, acylation and deacylation are indistinguishable for GES-5. The ertapenem-GES-2 crystal structure shows that only the core structure of the antibiotic interacts with the active site of the GES-2 beta-lactamase. The identical core structures of ertapenem, doripenem, and meropenem are likely responsible for the observed similarities in the kinetics with these carbapenems. The lack of a methyl group in the core structure of imipenem may provide a structural rationale for the increase in turnover of this carbapenem by the GES beta-lactamases. Our data also show that in GES-2 an extensive hydrogen-bonding network between the acyl-enzyme complex and the active site water attenuates activation of this water molecule, which results in poor deacylation by this enzyme.
Kinetic and Structural Requirements for Carbapenemase Activity in GES-Type beta-Lactamases.,Stewart NK, Smith CA, Frase H, Black DJ, Vakulenko SB Biochemistry. 2014 Dec 22. PMID:25485972[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Poirel L, Weldhagen GF, Naas T, De Champs C, Dove MG, Nordmann P. GES-2, a class A beta-lactamase from Pseudomonas aeruginosa with increased hydrolysis of imipenem. Antimicrob Agents Chemother. 2001 Sep;45(9):2598-603. PMID:11502535 doi:10.1128/AAC.45.9.2598-2603.2001
- ↑ Frase H, Shi Q, Testero SA, Mobashery S, Vakulenko SB. Mechanistic basis for the emergence of catalytic competence against carbapenem antibiotics by the GES family of beta-lactamases. J Biol Chem. 2009 Oct 23;284(43):29509-13. PMID:19656947 doi:10.1074/jbc.M109.011262
- ↑ Kotsakis SD, Miriagou V, Tzelepi E, Tzouvelekis LS. Comparative biochemical and computational study of the role of naturally occurring mutations at Ambler positions 104 and 170 in GES β-lactamases. Antimicrob Agents Chemother. 2010 Nov;54(11):4864-71. PMID:20696873 doi:10.1128/AAC.00771-10
- ↑ Frase H, Toth M, Champion MM, Antunes NT, Vakulenko SB. Importance of position 170 in the inhibition of GES-type β-lactamases by clavulanic acid. Antimicrob Agents Chemother. 2011 Apr;55(4):1556-62. PMID:21220532 doi:10.1128/AAC.01292-10
- ↑ Stewart NK, Smith CA, Frase H, Black DJ, Vakulenko SB. Kinetic and Structural Requirements for Carbapenemase Activity in GES-Type beta-Lactamases. Biochemistry. 2014 Dec 22. PMID:25485972 doi:http://dx.doi.org/10.1021/bi501052t
- ↑ Stewart NK, Smith CA, Frase H, Black DJ, Vakulenko SB. Kinetic and Structural Requirements for Carbapenemase Activity in GES-Type beta-Lactamases. Biochemistry. 2014 Dec 22. PMID:25485972 doi:http://dx.doi.org/10.1021/bi501052t
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