Peptidoglycan
Peptidoglycan or murein is a unique large macromolecule, a
The peptidoglycan layer is substantially thicker in
It is difficult to tell whether an organism is gram-positive or gram-negative using a microscope; Gram staining, created by Hans Christian Gram in 1884, is required. The bacteria are stained with several dyes such as crystal violet, iodine alcohol, and safranin. Gram positive cells are purple after staining, while Gram negative cells stain pink.[8]
Structure
The peptidoglycan layer within the bacterial cell wall is a
By enclosing the inner membrane, the peptidoglycan layer protects the cell from lysis caused by the turgor pressure of the cell. When the cell wall grows, it retains its shape throughout its life, so a rod shape will remain a rod shape, and a spherical shape will remain a spherical shape for life. This happens because the freshly added septal material of synthesis transforms into a hemispherical wall for the offspring cells.[9]
Cross-linking between amino acids in different linear amino sugar chains occurs with the help of the enzyme DD-transpeptidase and results in a 3-dimensional structure that is strong and rigid. The specific amino acid sequence and molecular structure vary with the bacterial species.[10]
The different peptidoglycan types of bacterial cell walls and their taxonomic implications have been described.[11] Archaea (domain Archaea[12]) do not contain peptidoglycan (murein).[13] Some Archaea contain pseudopeptidoglycan (pseudomurein, see below).[14]
-
The structure of peptidoglycan. NAG = N-acetylglucosamine (also called GlcNAc or NAGA), NAM = N-acetylmuramic acid (also called MurNAc or NAMA).
-
Gram-positive cell wall
-
Penicillin binding proteinforming cross-links in newly formed bacterial cell wall.
Peptidoglycan is involved in
In the course of early evolution, the successive development of boundaries (membranes, walls) protecting first structures of life against their environment must have been essential for the formation of the first cells (cellularisation).
The invention of rigid peptidoglycan (murein) cell walls in bacteria (domain Bacteria[12]) was probably the prerequisite for their survival, extensive radiation and colonisation of virtually all habitats of the geosphere and hydrosphere.[17][18]
Biosynthesis
The peptidoglycan monomers are synthesized in the cytosol and are then attached to a membrane carrier bactoprenol. Bactoprenol transports peptidoglycan monomers across the cell membrane where they are inserted into the existing peptidoglycan.[19]
- In the first step of peptidoglycan synthesis, EC 2.6.1.16 (GlmS), turns fructose 6-phosphate into glucosamine-6-phosphate.[21]
- In step two, an acetyl group is transferred from EC 5.4.2.10, catalyzed by GlmM.[21]
- In step three of the synthesis process, the N-acetyl-glucosamine-6-phosphate is isomerized, which will change N-acetyl-glucosamine-6-phosphate to EC 2.3.1.157, catalyzed by GlmU.[21]
- In step 4, the N-acetyl-glucosamine-1-phosphate, which is now a monophosphate, attacks EC 2.7.7.23, also catalyzed by GlmU, which is a bifunctional enzyme.[21]
- In step 5, some of the UDP-N-acetylglucosamine (UDP-GlcNAc) is converted to UDP-MurNAc (UDP-N-acetylmuramic acid) by the addition of a lactyl group to the glucosamine. Also in this reaction, the C3 hydroxyl group will remove a phosphate from the alpha carbon of EC 2.5.1.7, catalyzed by MurA.[21]
- In step 6, the enol is reduced to a "lactyl moiety" by NADPH in step six.EC 1.3.1.98, catalyzed by MurB.[21]
- In step 7, the UDP–MurNAc is converted to UDP-MurNAc pentapeptide by the addition of five amino acids, usually including the dipeptide D-alanyl-D-alanine.EC 6.3.2.13 by MurE.[21]
Each of these reactions requires the energy source ATP.[20] This is all referred to as Stage one.
Stage two occurs in the cytoplasmic membrane. It is in the membrane where a lipid carrier called bactoprenol carries peptidoglycan precursors through the cell membrane.
- EC 2.7.8.13 by MraY.[21]
- UDP-GlcNAc is then transported to MurNAc, creating Lipid-PP-MurNAc penta-GlcNAc (EC 2.4.1.227 by MurG.[21]
- Lipid II is transported across the membrane by flippase (MurJ), a discovery made in 2014 after decades of searching.[22] Once it is there, it is added to the growing glycan chain by the enzyme peptidoglycan glycosyltransferase (GTase, EC 2.4.1.129). This reaction is known as transglycosylation. In the reaction, the hydroxyl group of the GlcNAc will attach to the MurNAc in the glycan, which will displace the lipid-PP from the glycan chain.[20]
- In a final step, the penicillin-binding protein. Some versions of the enzyme also performs the glycosyltransferase function, while others leave the job to a separate enzyme.[21]
Pseudopeptidoglycan
In some archaea, i.e. members of the Methanobacteriales and in the genus Methanopyrus, pseudopeptidoglycan (pseudomurein) has been found.[14] In pseudopeptidoglycan the sugar residues are β-(1,3) linked N-acetylglucosamine and N-acetyltalosaminuronic acid. This makes the cell walls of such archaea insensitive to lysozyme.[23] The biosynthesis of pseudopeptidoglycan has been described.[24]
Recognition by immune system
Peptidoglycan recognition is an evolutionarily conserved process.[25] The overall structure is similar between bacterial species, but various modifications can increase the diversity. These include modifications of the length of sugar polymers, modifications in the sugar structures, variations in cross-linking or substitutions of amino acids (primarily at the third position).[25][26] The aim of these modifications is to alter the properties of the cell wall, which plays a vital role in pathogenesis.[25]
Peptidoglycans can be degraded by several enzymes (lysozyme, glucosaminidase, endopeptidase...[25]), producing immunostimulatory fragments (sometimes called muropeptides[27]) that are critical for mediating host-pathogen interactions.[26] These include MDP (muramyl dipeptide), NAG (N-acetylglucosamine) or iE-DAP (γ-d-glutamyl-meso-diaminopimelic acid).[25][27]
Peptidoglycan from intestinal bacteria (both pathogens and commensals) crosses the intestinal barrier even under physiological conditions.[27] Mechanisms through which peptidoglycan or its fragments enter the host cells can be direct (carrier-independent) or indirect (carrier-dependent), and they are either bacteria-mediated (secretion systems, membrane vesicles) or host cell-mediated (receptor-mediated, peptide transporters).[27] Bacterial secretion systems are protein complexes used for the delivery of virulence factors across the bacterial cell envelope to the exterior environment.[28] Intracellular bacterial pathogens invade eukaryotic cells (which may lead to the formation of phagolysosomes and/or autophagy activation), or bacteria may be engulfed by phagocytes (macrophages, monocytes, neutrophils...). The bacteria-containing phagosome may then fuse with endosomes and lysosomes, leading to degradation of bacteria and generation of polymeric peptidoglycan fragments and muropeptides.[27]
Receptors
Innate immune system senses intact peptidoglycan and peptidoglycan fragments using numerous PRRs (pattern recognition receptors) that are secreted, expressed intracellularly or expressed on the cell surface.[25]
Peptidoglycan recognition proteins
PGLYRPs are conserved from insects to mammals.[27] Mammals produce four secreted soluble peptidoglycan recognition proteins (PGLYRP-1, PGLYRP-2, PGLYRP-3 and PGLYRP-4) that recognize muramyl pentapeptide or tetrapeptide.[25] They can also bind to LPS and other molecules by using binding sites outside of the peptidoglycan-binding groove.[28] After recognition of peptidoglycan, PGLYRPs activate polyphenol oxidase (PPO) molecules, Toll, or immune deficiency (IMD) signalling pathways. That leads to production of antimicrobial peptides (AMPs).[28]
Each of the mammalian PGLYRPs display unique tissue expression patterns. PGLYRP-1 is mainly expressed in the granules of
PGLYRP-2 is primarily expressed by the
Recently, it has been discovered, that PGLYRPs (and also NOD-like receptors and peptidoglycan transporters) are highly expressed in the developing mouse brain.[30] PGLYRP-2 and is highly expressed in neurons of several brain regions including the prefrontal cortex, hippocampus, and cerebellum, thus indicating potential direct effects of peptidoglycan on neurons. PGLYRP-2 is highly expressed also in the cerebral cortex of young children, but not in most adult cortical tissues. PGLYRP-1 is also expressed in the brain and continues to be expressed into adulthood.[30]
NOD-like receptors
Probably the most well-known receptors of peptidoglycan are the
NOD1 is expressed by diverse cell types, including myeloid phagocytes, epithelial cells[25] and neurons.[30] NOD2 is expressed in monocytes and macrophages, epithelial intestinal cells, Paneth cells, dendritic cells, osteoblasts, keratinocytes and other epithelial cell types.[27] As cytosolic sensors, NOD1 and NOD2 must either detect bacteria that enter the cytosol, or peptidoglycan must be degraded to generate fragments that must be transported into the cytosol for these sensors to function.[25]
Recently, it was demonstrated that NLRP3 is activated by peptidoglycan, through a mechanism that is independent of NOD1 and NOD2.[27] In macrophages, N-acetylglucosamine generated by peptidoglycan degradation was found to inhibit hexokinase activity and induce its release from the mitochondrial membrane. It promotes NLRP3 inflammasome activation through a mechanism triggered by increased mitochondrial membrane permeability.[27]
NLRP1 is also considered as a cytoplasmic sensor of peptidoglycan. It can sense MDP and promote IL-1 secretion through binding NOD2.[28][26]
C-type lectin receptors (CLRs)
Toll-like receptors
The role of TLRs in direct recognition of peptidoglycan is controversial.[25] In some studies, has been reported that peptidoglycan is sensed by TLR2.[32] But this TLR2-inducing activity could be due to cell wall lipoproteins and lipoteichoic acids that commonly co-purify with peptidoglycan. Also variation in peptidoglycan structure in bacteria from species to species may contribute to the differing results on this topic.[25][27]
As vaccine or adjuvant
Peptidoglycan is immunologically active, which can stimulate immune cells to increase the expression of cytokines and enhance antibody-dependent specific response when combined with
Inhibition and degradation
Some
Other steps of peptidoglycan synthesis can also be targeted. The topical antibiotic bacitracin targets the utilization of C55-isoprenyl pyrophosphate. Lantibiotics, which includes the food preservative nisin, attack lipid II.[36]
Lysozyme, which is found in tears and constitutes part of the body's innate immune system exerts its antibacterial effect by breaking the β-(1,4)-glycosidic bonds in peptidoglycan (see above). Lysozyme is more effective in acting against Gram-positive bacteria, in which the peptidoglycan cell wall is exposed, than against Gram-negative bacteria, which have an outer layer of LPS covering the peptidoglycan layer.[31] Several bacterial peptidoglycan modifications can result in resistance to degradation by lysozyme. Susceptibility of bacteria to degradation is also considerably affected by exposure to antibiotics. Exposed bacteria synthesize peptidoglycan that contains shorter sugar chains that are poorly crosslinked and this peptidoglycan is then more easily degraded by lysozyme.[28]
See also
References
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