Background: Two groups of penicillin-destroying enzymes, the class A and class C β-lactamases, may have evolved from bacterial transpeptidases that transfer x-D-Ala-o-Ala peptides to the growing peptidoglycan during cell wall synthesis. Both the transpeptidases and the β-lactamases are acylated by β- lactam antibiotics such as penicillin, which mimic the peptide, but breakdown and removal of the antibiotic is much faster in the β-lactamases, which lack the ability to process D-Ala-D-Ala peptides. Stereochemical factors driving this evolution in specificity are examined. Results: We have compared the crystal structures of two classes of β-lactamases and a β-lactam-sensitive D-alanyl-D-alanine carboxypeptidase/transpeptidase (DD-peptidase). The class C β-lactamase is more similar to the DD-peptidase than to another β- lactamase of class A. Conclusions: The two classes of β lactamases appear to have developed from an ancestral protein along separate evolutionary paths. Structural differentiation of the β-lactamases from the DD-peptidases appears to follow differences in substrate shapes. The structure of the class A β-lactamase has been further optimized to exclude D-alanyl peptides and process penicillin substrates with near catalytic perfection.
Knox, J. R., Moews, P. C., & Frere, J. M. (1996). Molecular evolution of bacterial β-lactam resistance. Chemistry and Biology, 3(11), 937–947. https://doi.org/10.1016/S1074-5521(96)90182-9