
This peptide is further modified by attaching an additional peptide to the middle of the first one creating a branched structure. Finally the peptide of one of the polysaccharide molecules is attached to another to form the crosslink. The reaction is a transpeptidase reaction.
The mechanism is shown in the figure (Lee et al. 2003). The top structure (1) is a polysaccharideMurNAc-GlcNAc) with the first peptide already bound. Note that it ends in two D-Ala residues. The first step in the transpeptidase reaction involves binding of the enzyme (Enzyme-OH) to the D-Ala-D-Ala end of the chain. A reaction takes place in which one of the D-Alanine residues is released and the enzyme become attached to the end of the peptide (2).
In the second step, an adjacent peptidoglycan (purple) (3) with a branched structure is covalently linked to the first peptidoglycan forming a crosslink between the two polysaccharides.
Almost all bacteria have cell walls and they have transpeptidase enzymes that catalyze this reaction. The activity of this enzyme is inhibited by penicillins or β-lactams. Mondays Molecule #30 was Penicillin G, one of many different types of β-lactam that block cell wall formation and kill bacteria.
The mechanism of inhibition is well known. The β-lactam region of the drug resembles the D-Ala-D-Ala end of the peptide to which the transpeptidase enzyme binds. The structures are shown below.


The structures of several different transpeptidases have been solved. The enzymes are usually called penicillin-binding proteins or PBP's. Most bacteria have several related versions of PDB genes but all of the enzymes are inhibited by β-lactams.
The figure shows the structure of penicillin-binding protein 1a (PBP1a) from Streptococcus pneumoniae with the bound drug in gray in the grove in the lower right corner of the enzyme (Contreras-Martel et al. 2006). This form of the enzyme is inactive because the drug binds very tightly to the active site and blocks the reaction. That's how penicillin works.
Contreras-Martel, C., Job, V., Di Guilmi, A.M., Vernet, T., Dideberg, O. and Dessen, A. (2006) Crystal structure of penicillin-binding protein 1a (PBP1a) reveals a mutational hotspot implicated in beta-lactam resistance in Streptococcus pneumoniae. J. Mol. Biol. 355:684-96.
Lee, M., Hesek, D., Suvorov, M., Lee,W., Vakulenko, S. and Mobashery, S. (2003) A mechanism-based inhibitor targeting the DD-transpeptidase activity of bacterial penicillin-binding proteins. J. Am. Chem. Soc. 125:16322-16326.
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