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EcoSal Plus

Domain 2: Cell Architecture and Growth

Peptidoglycan: Structure, Synthesis, and Regulation

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  • Authors: Shambhavi Garde1,2, Pavan Kumar Chodisetti3,4, and Manjula Reddy5
  • Editor: James M. Slauch6
    Affiliations: 1: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India 500007; 2: These authors contributed equally.; 3: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India 500007; 4: These authors contributed equally.; 5: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India 500007; 6: The School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL
  • Received 21 September 2020 Accepted 21 December 2020 Published 20 January 2021
  • Address correspondence to Manjula Reddy, [email protected]
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  • Abstract:

    Peptidoglycan is a defining feature of the bacterial cell wall. Initially identified as a target of the revolutionary beta-lactam antibiotics, peptidoglycan has become a subject of much interest for its biology, its potential for the discovery of novel antibiotic targets, and its role in infection. Peptidoglycan is a large polymer that forms a mesh-like scaffold around the bacterial cytoplasmic membrane. Peptidoglycan synthesis is vital at several stages of the bacterial cell cycle: for expansion of the scaffold during cell elongation and for formation of a septum during cell division. It is a complex multifactorial process that includes formation of monomeric precursors in the cytoplasm, their transport to the periplasm, and polymerization to form a functional peptidoglycan sacculus. These processes require spatio-temporal regulation for successful assembly of a robust sacculus to protect the cell from turgor and determine cell shape. A century of research has uncovered the fundamentals of peptidoglycan biology, and recent studies employing advanced technologies have shed new light on the molecular interactions that govern peptidoglycan synthesis. Here, we describe the peptidoglycan structure, synthesis, and regulation in rod-shaped bacteria, particularly , with a few examples from and other diverse organisms. We focus on the pathway of peptidoglycan sacculus elongation, with special emphasis on discoveries of the past decade that have shaped our understanding of peptidoglycan biology.

  • Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020


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Peptidoglycan is a defining feature of the bacterial cell wall. Initially identified as a target of the revolutionary beta-lactam antibiotics, peptidoglycan has become a subject of much interest for its biology, its potential for the discovery of novel antibiotic targets, and its role in infection. Peptidoglycan is a large polymer that forms a mesh-like scaffold around the bacterial cytoplasmic membrane. Peptidoglycan synthesis is vital at several stages of the bacterial cell cycle: for expansion of the scaffold during cell elongation and for formation of a septum during cell division. It is a complex multifactorial process that includes formation of monomeric precursors in the cytoplasm, their transport to the periplasm, and polymerization to form a functional peptidoglycan sacculus. These processes require spatio-temporal regulation for successful assembly of a robust sacculus to protect the cell from turgor and determine cell shape. A century of research has uncovered the fundamentals of peptidoglycan biology, and recent studies employing advanced technologies have shed new light on the molecular interactions that govern peptidoglycan synthesis. Here, we describe the peptidoglycan structure, synthesis, and regulation in rod-shaped bacteria, particularly , with a few examples from and other diverse organisms. We focus on the pathway of peptidoglycan sacculus elongation, with special emphasis on discoveries of the past decade that have shaped our understanding of peptidoglycan biology.

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Figure 1

The figure depicts a few important discoveries pertaining to peptidoglycan structure and synthesis from the past century. Selected significant developments of the past decade are highlighted.

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Figure 2

(Top) Schematic of a rod-shaped cell with its peptidoglycan sacculus (blue mesh) located between the OM and IM. (Bottom) The zoomed-in rectangle depicts the composition of peptidoglycan. Glycan chains are made up of repeating disaccharide units of -acetylglucosamine (GlcNAc; gray hexagons) and -acetylmuramic acid (MurNAc; blue hexagons) with the peptide chains made up of amino acid residues (shaded blue circles), -alanine (-ala), -glutamic acid (-glu), meso-diaminopimelic acid (mDAP), and -alanine (-ala)–-ala. The glycan chains are linked to each other through peptide cross-linking between either -ala and mDAP or mDAP and mDAP residues to form a net-like sacculus. An OM lipoprotein (Braun’s lipoprotein, Lpp; orange helix) covalently tethers peptidoglycan to the OM. A GlcNAc-MurNAc pentapeptide is a single monomeric unit of peptidoglycan that is polymerized to form the functional sacculus. The terminal -ala is usually removed in the mature peptidoglycan.

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Figure 3

Bacteria grown with HADA (emission maximum, 450 nm) are visualized as described previously ( 73 , 74 ). Zones of fluorescence represent the sites of active peptidoglycan synthesis. Predominantly sidewall and septal peptidoglycan synthesis is observed in , Typhimurium, and . In and , peptidoglycan synthesis is seen at a single pole. Scale bar = 5 µm. (Image courtesy of Michael VanNieuwenhze, Yves Brun, and Erkin Kuru).

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Figure 4

Peptidoglycan precursors are synthesized in the cytoplasm by a series of enzymes, MurA, B, C, D, E, and F, that convert UDP-GlcNAc to form UDP-MurNAc-pentapeptide (also referred to as Park’s nucleotide), which is subsequently attached to the lipid transporter (undecaprenyl phosphate; C55P) by MraY to yield lipid-I that is converted to the final peptidoglycan precursor lipid-II, by addition of a GlcNAc moiety by MurG. A flippase MurJ transports lipid-II across the IM to the periplasm. Lipid-II is polymerized into the peptidoglycan by synthases, with C55P being recycled to the cytoplasm. TGase activity of RodA, FtsW, PBP1a, PBP1b, and MtgA catalyzes glycan polymerization, whereas TPase activity of PBP2, PBP3, PBP1a, and PBP1b contributes to peptide cross-link formation (refer to Box 1 ). Hydrolysis mediated by ,-endopeptidases, MepS, -M, and -H leads to cleavage of existing peptide cross-links to make space for the incorporation of nascent glycan strands. Anh-MurNAc (green hexagon) is the terminal residue in a glycan strand. The gray arrow indicates the direction of synthesis.

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Figure 5

(A) Schematic representation of elongation synthesis in a rod-shaped cell. The Rod complex (green circle) moves in helical fashion (purple) and synthesizes a scaffold, and aPBP-Lpos (orange dots) move in a diffusive manner (irregular blue lines) to fill the gaps, acting in concert to make a functional peptidoglycan sacculus. (B) Factors required for peptidoglycan elongation. Rod complex/elongasome is a multiprotein complex consisting of RodA, PBP2, RodZ, and MreBCD. The peptidoglycan synthase pair RodA-PBP2, guided by the MreBCD-RodZ complex, makes the peptidoglycan scaffold (red strands) around the cytoplasmic membrane. RodZ connects RodA-PBP2 with the cytoskeletal MreBCD to form the Rod complex, which moves circumferentially in the direction of peptidoglycan synthesis to form the scaffold (as shown in panel A). IM-localized PBP1a and PBP1b are activated by cognate OM lipoproteins LpoA and LpoB to complete the sidewall synthesis (black strands). LpoA and LpoB may traverse through the gaps in the peptidoglycan layer to interact and activate PBP1a and PBP1b. The activity of the major elongation-specific endopeptidase MepS may create space/gaps for interaction of aPBP-Lpo factors and to make space for incorporation of nascent peptidoglycan strands. MepS activity is kept in check by regulated proteolysis through its interaction with an adapter protein, NlpI, which brings the soluble periplasmic protease Prc. Nevertheless, the signal(s) that triggers sacculus expansion is not yet understood.

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Table 1

Inhibitors of peptidoglycan synthesis

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Table 2

Genes involved in cytosolic peptidoglycan precursor synthesis and turnover in

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020
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Table 3

Proteins involved in peptidoglycan synthesis in the periplasm

Citation: Garde S, Chodisetti P, Reddy M. 2021. Peptidoglycan: Structure, Synthesis, and Regulation, EcoSal Plus 2021; doi:10.1128/ecosalplus.ESP-0010-2020

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