title: Molecular evolution of bacterial beta-lactam resistance.
abstract: BACKGROUND
  Two groups of penicillin-destroying enzymes, the class A and class C beta-lactamases, may have evolved from bacterial transpeptidases that transfer X-D-Ala-D-Ala peptides to the growing peptidoglycan during cell wall synthesis. Both the transpeptidases and the beta-lactamases are acylated by beta-lactam antibiotics such as penicillin, which mimic the peptide, but breakdown and removal of the antibiotic is much faster in the beta-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 beta-lactamases and a beta-lactam-sensitive D-alanyl-D-alanine carboxy-peptidase/transpeptidase (DD-peptidase). The class C beta-lactamase is more similar to the DD-peptidase than to another beta-lactamase of class A.
  
  
  CONCLUSIONS
  The two classes of beta-lactamases appear to have developed from an ancestral protein along separate evolutionary paths. Structural differentiation of the beta-lactamases from the DD-peptidases appears to follow differences in substrate shapes. The structure of the class A beta-lactamase has been further optimized to exclude D-alanyl peptides and process penicillin substrates with near catalytic perfection.
authors.affiliation: Department of Molecular and Cell Biology, The University of Connecticut, Storrs, CT 06269-3125, USA. knox@uconnvm.uconn.edu.
authors.forename: J R
authors.initials: JR
authors.lastname: Knox
authors.forename: P C
authors.initials: PC
authors.lastname: Moews
authors.forename: J M
authors.initials: JM
authors.lastname: Frere
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D002384:Catalysis; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial / Q000235:genetics; D019143:Evolution, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases