Uncovering the activities, biological roles, and regulation of bacterial cell wall hydrolases and tailoring enzymes

Abstract

Bacteria account for 1000-fold more biomass than humans. They vary widely in shape and size. The morphological diversity of bacteria is due largely to the different peptidoglycan-based cell wall structures that encase bacterial cells. Although the basic structure of peptidoglycan is highly conserved, consisting of long glycan strands that are cross-linked by short peptide chains, the mature cell wall is chemically diverse. Peptidoglycan hydrolases and cell wall–tailoring enzymes that regulate glycan strand length, the degree of cross-linking, and the addition of other modifications to peptidoglycan are central in determining the final architecture of the bacterial cell wall. Historically, it has been difficult to biochemically characterize these enzymes that act on peptidoglycan because suitable peptidoglycan substrates were inaccessible. In this review, we discuss fundamental aspects of bacterial cell wall synthesis, describe the regulation and diverse biochemical and functional activities of peptidoglycan hydrolases, and highlight recently developed methods to make and label defined peptidoglycan substrates. We also review how access to these substrates has now enabled biochemical studies that deepen our understanding of how bacterial cell wall enzymes cooperate to build a mature cell wall. Such improved understanding is critical to the development of new antibiotics that disrupt cell wall biogenesis, a process essential to the survival of bacteria.

Structural Modeling of Cell Wall Peptidase CwpFM (EntFM) Reveals Distinct Intrinsically Disordered Extensions Specific to Pathogenic Bacillus cereus Strains

“…Additionally, the CW accommodates macromolecular components such as teichoic acid, lipoteichoic acids, polysaccharides and complex proteins like export secretion systems. CW integrity and plasticity need to be tuned to adapt readily to the bacterial cell cycle or to the changing environment, and its biosynthesis must be also highly regulated as CW disruption leads to bacterial cell death [2]. Accordingly, PG metabolism requires an exquisite and timely remodeling, organized by bacterial cell wall hydrolases (CWHs) [3].…”

“…Interestingly, due to their inherent flexibility and lack of structural characterization, the linker regions that connect the binding domains to the catalytic one have received little attention until now. Nevertheless, interest is increasing as they are shown to play a role in domains orientation or swapping, and dynamics that result in substrate specificity and affinity [1][2][3].…”

Ser/Thr kinase-dependent phosphorylation of the peptidoglycan hydrolase CwlA controls its export and modulates cell division inClostridioides difficile

“…Proper PG hydrolysis is essential for cell wall biogenesis. However, due to their destructive potential, PGH activity must be tightly regulated to ensure that hydrolases act when and where they should in coordination with PG synthesis to prevent CW damages (Do et al, 2020;Vermassen et al, 2019). In this study, we uncovered a novel and original mechanism for PG hydrolysis control by STK-dependent phosphorylation.…”

Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria

“…SweC and its binding partner SweD interact with the FtsE-FtsX integral membrane protein complex of the elongasome and acts as a mechanotransmission domain to activate the extracellular D,L-endopeptidase CwlO, which then degrades the distal load bearing peptidoglycan layers 88,94 . Overactivation of peptidoglycan hydrolases, such as CwlO, can lead to weakening of the peptidoglycan and cell lysis 95 . While sweC expression is repressed by Spo0A under sporulation conditions, proteins whose transcription is comparably repressed by Spo0A, such as PurT 96 , show no significant increase with 1 treatment.…”