Abstract
The cell walls of Gram-positive bacteria contain a variety of glycopolymers (CWGPs), a significant proportion of which are covalently linked to the peptidoglycan (PGN) scaffolding structure. Prominent CWGPs include wall teichoic acids of Staphylococcus aureus, streptococcal capsules, mycobacterial arabinogalactan, and rhamnose-containing polysaccharides of lactic acid bacteria. CWGPs serve important roles in bacterial cellular functions, morphology, and virulence. Despite evident differences in composition, structure and underlaying biosynthesis pathways, the final ligation step of CWGPs to the PGN backbone involves a conserved class of enzymes—the LytR-CpsA-Psr (LCP) transferases. Typically, the enzymes are present in multiple copies displaying partly functional redundancy and/or preference for a distinct CWGP type. LCP enzymes require a lipid-phosphate-linked glycan precursor substrate and catalyse, with a certain degree of promiscuity, CWGP transfer to PGN of different maturation stages, according to in vitro evidence. The prototype attachment mode is that to the C6-OH of N-acetylmuramic acid residues via installation of a phosphodiester bond. In some cases, attachment proceeds to N-acetylglucosamine residues of PGN—in the case of the Streptococcus agalactiae capsule, even without involvement of a phosphate bond. A novel aspect of LCP enzymes concerns a predicted role in protein glycosylation in Actinomyces oris. Available crystal structures provide further insight into the catalytic mechanism of this biologically important class of enzymes, which are gaining attention as new targets for antibacterial drug discovery to counteract the emergence of multidrug resistant bacteria.
Highlights
Introduction to the ReviewThis review covers what is currently known about the functions and structures of the LytR-CpsA-Psr (LCP) class of enzymes, which commonly transfer the reducing end of cell wall glycopolymers (CWGPs) of Gram-positive bacteria from a lipid carrier-bound CWGP intermediate to the peptidoglycan (PGN) backbone, usually via a phosphodiester linkage
These SCWPs are 5–20 kDa in size, composed of species-specific repeats [6,49], but lack repetitive alditol phosphates and phosphodiester bonds of wall teichoic acids (WTAs) [15,50,51], categorized as “non-classical” CWGPs. They contain 4,6-pyruvateketal-modifiedβ-D-N-acetylmannosamine (Pyr-β-D-ManpNAc) imparting a negative charge, which serves as a specific cell wall ligand for S-layer homology (SLH) domains that are usually present in triplicates at the termini of cell surface proteins [48,52,53]
Lc. lactis strains are covered by a RhaCWGP or sugar-phosphate polysaccharide pellicle (PSP), which is likely linked to the cell wall PGN via a “conventional” murein linkage unit as evident from the involvement of the TagO enzyme in its biosynthesis
Summary
This review covers what is currently known about the functions and structures of the LytR-CpsA-Psr (LCP) class of enzymes, which commonly transfer the reducing end of cell wall glycopolymers (CWGPs) of Gram-positive bacteria from a lipid carrier-bound CWGP intermediate to the peptidoglycan (PGN) backbone, usually via a phosphodiester linkage. PGN is composed of linear glycan backbone strands of alternatingly β-1,4-linked N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc) residues coupled via stem peptides that are attached to the MurNAc residues, resulting in a crosslinked, mesh-like framework. The role of PGN in bacterial survival has made PGN biosynthesis a target for important classes of antibiotics, including the glycopeptides (e.g., vancomycin) and the β-lactams (e.g., the penicillins, cephalosporins, and carbapenems) [7]. Both of these antibiotics inhibit PGN crosslinking, in different ways. Antibiotic inhibition of bacterial cell wall biosynthesis induces both common and compound-specific transcriptional responses, which both can be exploited to increase antibiotic susceptibility [13]
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