From the regulation of peptidoglycan synthesis to bacterial growth and morphology - PubMed (original) (raw)

Review

From the regulation of peptidoglycan synthesis to bacterial growth and morphology

Athanasios Typas et al. Nat Rev Microbiol. 2011.

Abstract

How bacteria grow and divide while retaining a defined shape is a fundamental question in microbiology, but technological advances are now driving a new understanding of how the shape-maintaining bacterial peptidoglycan sacculus grows. In this Review, we highlight the relationship between peptidoglycan synthesis complexes and cytoskeletal elements, as well as recent evidence that peptidoglycan growth is regulated from outside the sacculus in Gram-negative bacteria. We also discuss how growth of the sacculus is sensitive to mechanical force and nutritional status, and describe the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling.

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Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. Peptidoglycan synthesis and cleavage

The synthesis and attachment of a new peptidoglycan strand to the existing sacculus, with particular emphasis on the different synthetic and degrading enzymes. Precursors are synthesized in the cytoplasm, linked to the transport lipid (undecaprenyl phosphate) and flipped accross the inner membrane by FtsW–RodA. A glycosyltransferase (GTase) catalyses polymerization of a nascent peptidoglycan chain from lipid II precursor at the inner membrane, followed by attachment of the new chain to the sacculus by a DD-transpeptidase (DD-TPase). Peptides are trimmed by DD-, LD-and DL-carboxypeptidases (CPases), and crosslinks are cleaved by the DD-and LD-endopeptidases (EPases). Amidases remove peptides from glycan chains, and _exo_-or endo-specific lytic transglycosylases (LTs) cleave in the glycan chain to form 1,6-anhydro-_N_-acetylmuramic acid (anhMurNAc) residues, which are the hallmark of glycan chain ends. LD-TPases are responsible for the formation of LD-crosslinks, the attachment of the major outer-membrane lipoprotein (Lpp), which is anchored in the outer membrane, and the binding of unusual D-amino acids. The number of known Escherichia coli enzymes for each group is shown in brackets, but this is probably an underestimate, as even in E. coli not all players are known and/or characterized. Alr, Ala racemase, biosynthetic; DadX, Ala racemase, catabolic; DdlA, D-Ala–D-Ala ligase A; GlcNAc, _N_-acetylglucosamine; _meso_-Dap, _meso_-diaminopimelic acid; MraY, UDP-MurNAc-pentapeptide phosphotransferase; MurA, UDP-GlcNAc enolpyruvyl transferase; MurB, UDP-MurNAc dehydrogenase; MurC, UDP-MurNAc–L-Ala ligase; MurD, UDP-MurNAc-L-Ala–D-Glu ligase; MurE, UDP-MurNAc-L-Ala-D-Glu-_meso_-Dap ligase; MurF, UDP-MurNAc-tripeptide–D-alanyl-D-Ala ligase; MurG, UDP-GlcNAc-undecaprenoyl-pyrophosphoryl-MurNAc-pentapeptide transferase; Murl, Glu racemase; PEP, phosphoenolpyruvate.

Figure 2

Figure 2. Different peptidoglycan synthesis complexes are active at different stages of the Escherichia coli cell cycle

As shown in the upper left panel, MreB and associated membrane proteins control or position the peptidoglycan synthases penicillin-binding protein 1A (PBP1A) and PBP2, as well as still-unknown hydrolases (Hyd), during the ‘dispersed’ mode of elongation. As illustrated in the upper right panel, FtsZ and other early cell division proteins control the elongation-specific peptidoglycan synthesis complex during a ‘preseptal’ mode of elongation. It is not known whether MreB and associated proteins participate in preseptal elongation. Finally, as depicted in the lower panel, the cell division complex contains essential, inner membrane-localized cell division proteins, the peptidoglycan synthases PBP1B and PBP3, and amidase enzymes (Ami) with their activators, as well as proteins of the Tol–Pal complex for constriction of the outer membrane. Activity of the PBPs is regulated in part by outer membrane-anchored lipoproteins such as LpoA and LpoB. LT, lytic transglycosylase.

Figure 3

Figure 3. Force generation by cytoskeletal elements

a | Crescentin (CreS) reduces the strain at one side of the cell, causing Caulobacter crescentusto grow in a bent shape. Detachment of the CreS filament from the membrane (on addition of mecillinam) results in rapid loss of the filament’s stretched form but does not cause an instant change in cell shape. Cells lacking CreS grow with a straight shape. b | FtsZ generates an inwardly directed constriction force in vesicle tubes and presumably also in the cell. c | Depolymerization of MreB filaments by addition of the drug A22 (_S_-(3,4-dichlorobenzyl)isothiourea) reduces the stiffness of Escherichia coli cells.

Figure 4

Figure 4. Species-specific non-catalytic regions in penicillin-binding proteins

Different class A penicillin-binding proteins (PBPs) in comparison with Escherichia coli PBP1A and PBP1B. Predicted or known transmembrane domains are shown in brown, newly evolved domains in E. coli PBP1A and PBP1B in dark blue and other species-specific regions with no function prediction in grey. Glycosyltransferase (GT) and transpeptidase (TP) domains are labelled, along with the fibronectin type 3 (FN3) domain and the ribosomal protein S1-like RNA-binding (S1) domains. The species-specific regions with no function prediction in the two Myxococcus xanthus proteins contain an S1 domain and are only conserved in Stigmatella and Myxococcus spp., whereas the analogous regions in the two Bacillus subtilis proteins consist of one that is unique in B. subtilis (the carboxy-terminal region in PBP1) and one that is more conserved among the bacilli (the domain in PBP4); the FN3 domain found in PBP1 is also conserved only in bacilli. ODD, outer-membrane PBP1A docking domain; UB2H, UvrB domain 2 homologue.

Figure 5

Figure 5. Regulation of peptidoglycan synthesis by outer-membrane proteins

a | Side view of the Escherichia coli cell envelope with the crystal structure of penicillin-binding protein 1B (PBP1B; Protein Data Bank accession 3FWM) and the distances between the inner membrane, peptidoglycan (PG) and outer membrane drawn to scale. The glycosyltransferase (GTase) and transpeptidase (TPase) domains are shown. The structure of the activator protein for PBP1B, LpoB, is unknown. LpoB is anchored in the outer membrane and interacts with the PBP1B UB2H (UvrB domain 2 homologue) domain, which is situated between the inner membrane and the PG layer, not more than ~60 Å away from the inner membrane. The distance from the inner membrane to the PG is ~90 Å. b | A hypothetical self-repair mechanism to maintain a homogeneous peptidoglycan layer. The cell on the left has a non-homogeneous peptidoglycan layer consisting of large and small pores. Pore size-responsive activation of peptidoglycan synthase activity results in a more homogeneous peptidoglycan layer (on the right). c | A hypothetical homeostatic mechanism to balance the peptidoglycan growth rate with the overall cellular growth rate. When the peptidoglycan growth rate falls behind or exceeds that of overall cell growth, the peptidoglycan net stretches or relaxes, respectively. The resulting change in pore size alters the efficiency with which Lpo proteins can activate peptidoglycan synthases and therefore re-aligns the peptidoglycan growth rate with the overall cellular growth rate.

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