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. 2010 Jul 8;53(13):4813-29.
doi: 10.1021/jm100086u.

Host-guest chemistry of the peptidoglycan

Jed F Fisher  1 , Shahriar Mobashery
Affiliations

Host-guest chemistry of the peptidoglycan

Jed F Fisher et al. J Med Chem. .
No abstract available

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Figures

Figure 1
Figure 1
Visualization of the external peptidoglycan surface of Gram-positive bacteria by the use of fluorescently-labeled peptidoglycan-binding antibiotics. These fluorescent microscopy images, reproduced from the study by Tiyanont et al. Proc. Natl Acad. Sci. U. S. A. 2006, 103, 11033–11038 © 2006 National Academy of Sciences, show rod-shaped B. subtilis (the bacterium is approximately 2 µm in length) bacteria stained with fluorescein-labeled ramoplanin. The peptidoglycan is intensely stained at the newly forming division septum, and to a lesser extent on the sidewalls and the old pole. These locations coincide with the sub-cellular locations of Lipid II, the key biosynthetic precursor of the peptidoglycan (see Scheme 1). The sidewall staining is suggestive of a helical pattern for peptidoglycan growth during sidewall elongation.
Figure 2
Figure 2
Computational stereo structure of the [NAG-NAM]2 structure (see Scheme 2) in complex with the human PGRP-1® peptidodglycan recognition protein, based on an X-ray structure of a smaller synthetic fragment bound to the protein (PDB Code 2EAX). The approximate diameter of the protein is 4 nm. The perspective shown for the protein orients the peptidoglycan cleft from top to bottom.
Figure 3
Figure 3
The catalytic module of the Cpl-1 endolysin in complex with peptidoglycan (PDB Code 2J8G). A comparison of this protein structure with those of Figs. 2 and 4 emphasizes the evolutionary convergence of different protein motifs for the purpose of peptidoglycan binding.
Figure 4
Figure 4
Complex of E. coli PBP6 (catalytic domain of monomer B, PDB Code 3ITB) with the peptidoglycan structure that is shown in Scheme 7.
Figure 5
Figure 5
Stereo view of the PBP6 acyl-enzyme complex compared to that of the deacylation transition state. A PBP5 transition-state analog structure (PDB Code 1Z6F) is superimposed onto the PBP6 structure with ampicillin (PDB Code 3ITA), showing active site residues 39, 40, 43, 108 and 210. The transition-state analog and the catalytic serine of PBP5 are shown in blue, whereas ampicillin and PBP6 are shown in pink. Water molecules are represented as red spheres. Key distances are displayed as dashed lines. The amine group of Lys43 engages in hydrogen bonds with two water molecules in the PBP6 acyl-enzyme complex. The distance between the β-lactam-thiazolidine bridging carbon atom of ampicillin, and the boronic acid oxygen of the superimposed transition state analog, is only 1.97 Å. This carbon presents a steric impediment to hydrolytic deacylation.,
Scheme 1
Scheme 1
The cross-linking event in peptidoglycan biosynthesis by the Gram-positive bacterium S. aureus. The structure of the immediate biosynthetic precursor for the peptidoglycan of S. aureus, Lipid II-Gly5 is shown as the bottom structure. The cross-linking event is highlighted within the hashed-edged box shown in the center right. This stem cross-linking event, wherein the amine terminus of the pentaaglycine displaces the d-alanine terminus on the stem of an adjacent glycan strand, is catalyzed by the transpeptidase domain of a high molecular mass PBP enzyme. This reaction proceeds through an acyl-enzyme intermediate (not depicted). Lipid II-Gly5 participation in transpeptidase cross-linking is shown only for the purpose of illustration. Peptide stem cross-linking almost certainly occurs subsequent to Lipid II-Gly5-dependent, transglycosylase-catalyzed elongation of the glycan strand. The inset box (lower right) shows the β-lactam antibiotic structure as a mimetic of a conformation of the -d-Ala-d-Ala stem used in the cross-linking.
Scheme 2
Scheme 2
The synthetic [NAG-NAM]2 mimetic of the non-crosslinked peptidoglycan of the cell wall, used for the NMR determination of the solution conformation of a peptidoglycan strand.
Scheme 3
Scheme 3
Structures of vancomycin (left) and oritavancin (right).
Scheme 4
Scheme 4
Hydrogen-bonding interactions in the -d-Ala-d-Ala peptidoglycan-vancomycin host-guest complex (left) compared to the -d-Ala-d-Lac peptidoglycan-vancomycin host-guest complex (right). The loss of a key hydrogen bond, and its replacement by unfavorable non-bonding repulsive interactions, is indicated by the red-colored arrows in the -d-Ala-d-Lac depsipeptide complex.
Scheme 5
Scheme 5
Peptidoglycan fragmentation leads to NAG-NAM segments, which are transported across plasma membrane to initiate the recycling of these segments and gene induction for production of the β-lactamase enzyme.
Scheme 6
Scheme 6
Substrate specificity, measured by kcat/Km, for Citrobacter freundii AmpD amidase-catalyzed amide bond hydrolysis (cleavage point indicated by the arrows) of three anhydromuramyl muropeptide structures.
Scheme 7
Scheme 7
Structure of the synthetic peptidoglycan, used in the determination of the crystal structure of a Michaelis complex-like structure with E. coli PBP6. The red-colored hydrogen bonds drawn to the (scissile) amide carbonyl of the penultimate d-Ala residue indicates its occupancy of the oxyanion hole of the active site.
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