The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases
Open Access
- 11 December 2019
- journal article
- review article
- Published by MDPI AG in Biomolecules
- Vol. 9 (12), 854
- https://doi.org/10.3390/biom9120854
Abstract
Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme’s active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM–type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl–enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.Keywords
This publication has 85 references indexed in Scilit:
- Communication between the active site and the allosteric site in class A beta-lactamasesComputational Biology and Chemistry, 2013
- Network Models of TEM β-Lactamase Mutations Coevolving under Antibiotic Selection Show Modular Structure and Anticipate Evolutionary TrajectoriesPLoS Computational Biology, 2011
- Transpeptidase-Mediated Incorporation of d-Amino Acids into Bacterial PeptidoglycanJournal of the American Chemical Society, 2011
- Three Decades of β-Lactamase InhibitorsClinical Microbiology Reviews, 2010
- Multiple Molecular Dynamics Simulations of TEM β-Lactamase: Dynamics and Water Binding of the Ω-LoopBiophysical Journal, 2009
- NMR Dynamics of PSE-4 β-Lactamase: An Interplay of ps-ns Order and μs-ms Motions in the Active SiteBiophysical Journal, 2009
- Genetic and Structural Insights into the Dissemination Potential of the Extremely Broad-Spectrum Class A β-Lactamase KPC-2 Identified in an Escherichia coli Strain and an Enterobacter cloacae Strain Isolated from the Same Patient in FranceAntimicrobial Agents and Chemotherapy, 2008
- Evolution of an Antibiotic Resistance Enzyme Constrained by Stability and Activity Trade-offsJournal of Molecular Biology, 2002
- TEM β-Lactamase Mutants Hydrolysing Third-generation Cephalosporins: A Kinetic and Molecular Modelling AnalysisJournal of Molecular Biology, 1994
- Evolution of antibiotic resistance: several different amino acid substitutions in an active site loop alter the substrate profile of β‐lactamaseMolecular Microbiology, 1994