Bacterial cell walls are made of peptidoglycan [Bacteria Have Cell Walls]. In order to form a rigid structure, the polysaccharide chains (glycans) are linked together by peptide crosslinks. The first step in the formation of the crosslinks involves attachment of a short five residue peptide to the MurNAc sugar in the polysaccharide. This peptide ends in two D-Alanine (D-Ala) residues.
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.
A typical penicillin is shown at the top of the figure. The business part of the molecule is the β-lactam moiety and the "R" represents various groups that can be bound to create different penicillin drugs. The structure of D-Ala-D-Ala is 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.