Penicillin and Beyond: Evolution, Protein Fold, Multimodular Polypeptides, and Multiprotein Complexes

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Abstract
As the protein sequence and structure databases expand, the relationships between proteins, the notion of protein superfamily, and the driving forces of evolution are better understood. Key steps of the synthesis of the bacterial cell wall peptidoglycan are revisited in light of these advances. The reactions through which the d-alanyl-d-alanine depeptide is formed, utilized, and hydrolyzed and the sites of action of the glycopeptide and β-lactam antibiotics illustrate the concept according to which new enzyme functions evolve as a result of tinkering of existing proteins. This occurs by the acquisition of local structural changes, the fusion into multimodular polypeptides, and the association into multiprotein complexes.