cleft is occupied by the Ser35-Thr36-Thr37-Lys38 tetrad, which includes the nucleophilic Ser35 residue at the amino-terminal end of helix α2. One side of the cavity is defined by the Ser96-Gly97-Cys98 loop connecting helices α4 and α5. The Lys213-Thr214-Gly215 triad lies on strand β3 on the opposite side of the cavity. The backbone NH group of the essential Ser35 residue and that of Ser216 downstream from the motif Lys213-Thr214-Gly215 occupy positions that are compatible with the oxyanion hole function required for catalysis. The enzyme is classified as a DD-transpeptidase because the susceptible peptide bond of the carbonyl donor extends between two carbon atoms with the D-configuration. Biological Function All bacteria possess at least one, most often several, monofunctional serine DD-peptidases. Disease Relevance This enzyme is an excellent drug target because it is essential, is accessible from the periplasm, and has no equivalent in mammalian cells. DD-transpeptidase is the target protein of β-lactam antibiotics (e.g. penicillin) This is because the structure of the β-lactam closely resembles the D-ala-D-ala residue. β-lactams exert their effect by competitively inactivating the serine DD-transpeptidase catalytic site. Penicillin is a cyclic analogue of the D-Ala-D-Ala terminated carbonyl donors, therefore in the presence of this antibiotic, the reaction stops at the level of the serine ester-linked penicilloyl enzyme. Thus β-lactam antibiotics force these enzymes to behave like penicillin binding proteins. Kinetically, the interaction between the DD-peptidase and beta-lactams is a three-step reaction: Beta-Iactams may form an adduct E-I* of high stability with DD-transpeptidase. The half life of this adduct is around hours, whereas the half-life of the normal reaction is in the order of milliseconds. The interference with the enzyme processes responsible for cell wall formation results in cellular lysis and death due to the triggering of the autolytic system in the bacteria. See also Vancomycin, an antibiotic that binds the D-ala-D-ala residues, inhibiting elongation via glycosyltransferase References External links The MEROPS online database for peptidases and their inhibitors: S11.001 EC 3.4.16 Bacteria