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Molecular evolution of bacterial beta-lactam resistance
J R Knox1, P C Moews, J M Frere
1Department of Molecular and Cell Biology, The University of Connecticut, Storrs, CT 06269-3125, USA. knox@uconnvm.uconn.edu.
Chemistry & Biology
|November 1, 1996
Summary
Beta-lactamases evolved from bacterial transpeptidases. Structural analysis reveals class C beta-lactamases are more similar to transpeptidases than class A, suggesting distinct evolutionary paths driven by substrate shape.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Structural Biology
Background:
- Beta-lactamases, enzymes that degrade penicillin, may have evolved from bacterial transpeptidases involved in cell wall synthesis.
- Both enzyme types are acylated by beta-lactam antibiotics, but beta-lactamases process them faster due to an inability to handle D-Ala-D-Ala peptides.
Purpose of the Study:
- To examine the stereochemical factors driving the evolution of beta-lactamase specificity.
- To compare the evolutionary divergence of class A and class C beta-lactamases from their ancestral transpeptidases.
Main Methods:
- Comparative analysis of crystal structures of class A and class C beta-lactamases.
- Structural comparison with a beta-lactam-sensitive D-alanyl-D-alanine carboxy-peptidase/transpeptidase (DD-peptidase).
Main Results:
- Class C beta-lactamase exhibits greater structural similarity to DD-peptidase than class A beta-lactamase.
- Structural differences between beta-lactamases and DD-peptidases correlate with substrate shape preferences.
Conclusions:
- Class A and class C beta-lactamases likely evolved from a common ancestor via separate evolutionary trajectories.
- Class A beta-lactamase structure is highly optimized for processing penicillin, excluding D-alanyl peptides.
- Evolutionary divergence is driven by changes in substrate specificity, particularly concerning D-Ala-D-Ala peptides.