Array ( [0] => {{Short description|Polymer in bacterial cell walls}} [1] => {{Distinguish|glycopeptide|proteoglycan|glycoprotein}} [2] => '''Peptidoglycan''' or '''murein''' is a unique large macromolecule, a [[polysaccharide]], consisting of sugars and [[amino acid]]s that forms a mesh-like layer (sacculus) that surrounds the [[bacterial]] cytoplasmic membrane.{{Cite book |last1=Madigan |first1=Michael T. |title=Brock Biology of Microorganisms |last2=Martinko |first2=John M. |last3=Bender |first3=Kelly S. |last4=Buckley |first4=Daniel H. |last5=Stahl |first5=David A. |publisher=Pearson Education Limited |year=2015 |isbn=978-1-292-01831-7 |edition=14 |location=Boston |pages=66–67}} The sugar component consists of alternating residues of β-(1,4) linked [[N-Acetylglucosamine|''N''-acetylglucosamine]] (NAG) and [[N-Acetylmuramic acid|''N''-acetylmuramic acid]] (NAM). Attached to the ''N''-acetylmuramic acid is an [[oligopeptide]] chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer.{{cite web | vauthors = Mehta A | date = 20 March 2011 | work = PharmaXChange.info | url = http://pharmaxchange.info/press/2011/03/animation-of-synthesis-of-peptidoglycan-layer/| title = Animation of Synthesis of Peptidoglycan Layer}} Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the [[osmotic pressure]] of the [[cytoplasm]]. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.{{cite journal | vauthors = Belgrave AM, Wolgemuth CW | title = Elasticity and biochemistry of growth relate replication rate to cell length and cross-link density in rod-shaped bacteria | journal = Biophysical Journal | volume = 104 | issue = 12 | pages = 2607–2611 | date = June 2013 | pmid = 23790368 | pmc = 3686348 | doi = 10.1016/j.bpj.2013.04.028 | bibcode = 2013BpJ...104.2607B }} [3] => [4] => The peptidoglycan layer is substantially thicker in [[Gram-positive]] [[bacteria]] (20 to 80 nanometers) than in [[Gram-negative]] bacteria (7 to 8 nanometers).{{cite web | vauthors=Purcell A | title=Bacteria | date= 18 March 2016 | url= https://basicbiology.net/micro/microorganisms/bacteria | publisher= Basic Biology }} Depending on pH growth conditions, the peptidoglycan forms around 40 to 90% of the [[cell wall]]'s [[dry matter|dry weight]] of Gram-positive bacteria but only around 10% of Gram-negative strains. Thus, presence of high levels of peptidoglycan is the primary determinant of the characterisation of bacteria as [[Gram-positive bacteria|Gram-positive]].{{cite encyclopedia | vauthors = Hogan CM | date = 12 October 2014 | url = https://editors.eol.org/eoearth/wiki/Bacteria | title = Bacteria | encyclopedia = Encyclopedia of Earth | veditors = Draggan S, Cleveland CJ | publisher = National Council for Science and the Environment | location = Washington DC }} In Gram-positive strains, it is important in attachment roles and [[serotyping]] purposes.{{cite book |vauthors=Salton MR, Kim KS | title = Structure. ''In:'' Baron's Medical Microbiology| editor = Baron S| display-editors = etal| edition = 4th | publisher = Univ of Texas Medical Branch | year = 1996 | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.289#297 | isbn=978-0-9631172-1-2 | chapter = Structure| pmid = 21413343}} For both Gram-positive and Gram-negative bacteria, particles of approximately 2 nm can pass through the peptidoglycan.{{cite journal | vauthors = Demchick P, Koch AL | title = The permeability of the wall fabric of Escherichia coli and Bacillus subtilis | journal = Journal of Bacteriology | volume = 178 | issue = 3 | pages = 768–773 | date = February 1996 | pmid = 8550511 | pmc = 177723 | doi = 10.1128/jb.178.3.768-773.1996 }} [5] => [6] => It is difficult to tell whether an organism is gram-positive or gram-negative using a microscope; [[Gram stain]]ing, 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.{{cite web |title=2.3: The Peptidoglycan Cell Wall |url=https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Kaiser)/Unit_1%3A_Introduction_to_Microbiology_and_Prokaryotic_Cell_Anatomy/2%3A_The_Prokaryotic_Cell_-_Bacteria/2.3%3A_The_Peptidoglycan_Cell_Wall |website=Biology LibreTexts |access-date=5 November 2023 |language=en |date=1 March 2016}} [7] => [8] => == Structure == [9] => [[Image:Peptidoglycan en.svg|thumb|Peptidoglycan.]] [10] => The peptidoglycan layer within the bacterial cell wall is a [[crystal lattice]] structure formed from linear chains of two alternating amino [[sugar]]s, namely [[N-Acetylglucosamine|''N''-acetylglucosamine]] (GlcNAc or NAG) and [[N-Acetylmuramic acid|''N''-acetylmuramic acid]] (MurNAc or NAM). The alternating sugars are connected by a β-(1,4)-[[glycosidic bond]]. Each MurNAc is attached to a short (4- to 5-residue) [[amino acid]] chain, containing [[alanine|L-alanine]], [[glutamic acid|D-glutamic acid]], [[meso-diaminopimelic acid|''meso''-diaminopimelic acid]], and [[alanine|D-alanine]] in the case of ''[[Escherichia coli]]'' (a Gram-negative bacterium) or [[alanine|L-alanine]], [[glutamine|D-glutamine]], [[lysine|L-lysine]], and [[D-amino acid|D-alanine]] with a 5-[[glycine]] interbridge between tetrapeptides in the case of ''[[Staphylococcus aureus]]'' (a Gram-positive bacterium). Peptidoglycan is one of the most important sources of [[D-amino acid]]s in nature.{{cn|date=May 2023}} [11] => [12] => By enclosing the inner membrane, the peptidoglycan layer protects the cell from [[lysis]] caused by the [[Turgor pressure|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.{{cite journal | vauthors = Huang KC, Mukhopadhyay R, Wen B, Gitai Z, Wingreen NS | title = Cell shape and cell-wall organization in Gram-negative bacteria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 49 | pages = 19282–19287 | date = December 2008 | pmid = 19050072 | pmc = 2592989 | doi = 10.1073/pnas.0805309105 | doi-access = free | bibcode = 2008PNAS..10519282H }} [13] => [14] => [[Cross-link]]ing between [[amino acid]]s 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]].{{cite book | veditors = Ryan KJ, Ray CG | title = Sherris Medical Microbiology | edition = 4th | publisher = McGraw Hill | year = 2004 | isbn = 978-0-8385-8529-0 }} [15] => [16] => The different peptidoglycan types of bacterial cell walls and their taxonomic implications have been described.{{cite journal | vauthors = Schleifer KH, Kandler O | title = Peptidoglycan types of bacterial cell walls and their taxonomic implications | journal = Bacteriological Reviews | volume = 36 | issue = 4 | pages = 407–477 | date = December 1972 | pmid = 4568761 | pmc = 408328 | doi = 10.1128/MMBR.36.4.407-477.1972 | author-link2 = Otto Kandler }} [[Archaea]] ([[Domain (biology)|domain]] ''Archaea''{{cite journal | vauthors = Woese CR, Kandler O, Wheelis ML | title = Towards a natural system of organisms: proposal for the domains Archaea, Bacteria, and Eucarya | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 12 | pages = 4576–4579 | date = June 1990 | pmid = 2112744 | pmc = 54159 | doi = 10.1073/pnas.87.12.4576 | bibcode = 1990PNAS...87.4576W | doi-access = free | author-link2 = Otto Kandler | author-link = Carl Woese }}) do not contain peptidoglycan (murein).{{cite journal | vauthors = Kandler O, Hippe H | title = Lack of peptidoglycan in the cell walls of Methanosarcina barkeri | journal = Archives of Microbiology | volume = 113 | issue = 1–2 | pages = 57–60 | date = May 1977 | pmid = 889387 | doi = 10.1007/BF00428580 | bibcode = 1977ArMic.113...57K | s2cid = 19145374 | author-link = Otto Kandler }} Some Archaea contain [[pseudopeptidoglycan]] (pseudomurein, see below).{{cite journal | vauthors = Kandler O, König H | title = Cell wall polymers in Archaea (Archaebacteria) | journal = Cellular and Molecular Life Sciences | volume = 54 | issue = 4 | pages = 305–308 | date = April 1998 | pmid = 9614965 | doi = 10.1007/s000180050156 | s2cid = 13527169 | author-link = Otto Kandler }} [17] => [18] => [19] => File:Mureine.svg|The structure of peptidoglycan. NAG = [[N-Acetylglucosamine|''N''-acetylglucosamine]] (also called GlcNAc or NAGA), NAM = [[N-Acetylmuramic acid|''N''-acetylmuramic acid]] (also called MurNAc or NAMA). [20] => File:Gram-positive cellwall-schematic.png|[[Gram-positive]] [[cell wall]] [21] => File:PBP catalysis.svg|[[Penicillin binding protein]] forming cross-links in newly formed bacterial cell wall. [22] => Peptidoglycan is involved in [[binary fission]] during bacterial cell reproduction. [[L-form bacteria]] and [[mycoplasma]]s, both lacking peptidoglycan cell walls, do not proliferate by binary fission, but by a [[budding]] mechanism.{{cite journal | vauthors = Kandler G, Kandler O | title = [Studies on morphology and multiplication of pleuropneumonia-like organisms and on bacterial L-phase, I. Light microscopy] | language = German | journal = Archiv für Mikrobiologie | volume = 21 | issue = 2 | pages = 178–201 | date = 1954 | pmid = 14350641 | doi = 10.1007/BF01816378 | trans-title = Studies on morphology and multiplication of pleuropneumonia-like organisms and on bacterial L-phase, I. Light microscopy (now mycoplasmas and L-form bacteria) | s2cid = 21257985 | others = (Article in English available) | author-link2 = Otto Kandler }}{{cite journal | vauthors = Leaver M, Domínguez-Cuevas P, Coxhead JM, Daniel RA, Errington J | title = Life without a wall or division machine in Bacillus subtilis | journal = Nature | volume = 457 | issue = 7231 | pages = 849–853 | date = February 2009 | pmid = 19212404 | doi = 10.1038/nature07742 | others = [see also Erratum, 23 July 2009, Nature, vol. 460, p.538] | bibcode = 2009Natur.457..849L | s2cid = 4413852 }} [23] => [24] => 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 ([[Cellularization|cellularisation]]). [25] => [26] => The invention of rigid peptidoglycan (murein) cell walls in bacteria (domain ''Bacteria'') was probably the prerequisite for their survival, extensive radiation and colonisation of virtually all habitats of the geosphere and hydrosphere.{{Cite book | vauthors = Kandler O |title=Early Life on Earth. Nobel Symposium 84 |publisher=Columbia U.P. |year=1994 |isbn=978-0-231-08088-0 | veditors = Bengtson S |location=New York |pages=221–270 |chapter=The early diversification of life |author-link=Otto Kandler}}{{Cite book | vauthors = Kandler O |chapter-url=https://books.google.com/books?id=FtSzl4iastsC&q=Otto+Kandler%3A+The+early+diversification+of+life+and+the+origin+of+the+three+domains%3A+A+proposal.+In%3A+J%C3%BCrgen+Wiegel%2C+Michael+%E2%80%8EW.W.+Adams+%28Hrsg.%29%3A+Thermophiles&pg=PA19 |title=Thermophiles: The keys to molecular evolution and the origin of life? |publisher=Taylor and Francis Ltd. |year=1998 |isbn=978-0-203-48420-3 | veditors = Wiegel J, Adams MW |location=London |pages=19–31 |chapter=The early diversification of life and the origin of the three domains: A proposal |author-link=Otto Kandler }} [27] => [28] => == Biosynthesis == [29] => 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.{{cite web |url=http://student.ccbcmd.edu/courses/bio141/lecguide/unit1/prostruct/cw.html |title= The Prokaryotic Cell: Bacteria |access-date=1 May 2011 |archive-url= https://web.archive.org/web/20100726231059/http://student.ccbcmd.edu/courses/bio141/lecguide/unit1/prostruct/cw.html |archive-date=26 July 2010 }} [30] => [31] => # In the first step of peptidoglycan synthesis, [[glutamine]], which is an amino acid, donates an amino group to a sugar, [[fructose 6-phosphate]]. This reaction, catalyzed by [[EC 2.6.1.16]] (GlmS), turns fructose 6-phosphate into [[glucosamine-6-phosphate]].{{cite journal | vauthors = Otten C, Brilli M, Vollmer W, Viollier PH, Salje J | title = Peptidoglycan in obligate intracellular bacteria | journal = Molecular Microbiology | volume = 107 | issue = 2 | pages = 142–163 | date = January 2018 | pmid = 29178391 | doi = 10.1111/mmi.13880 | pmc = 5814848 | doi-access = free }} [32] => # In step two, an acetyl group is transferred from [[acetyl CoA]] to the amino group on the glucosamine-6-phosphate creating [[N-acetyl-glucosamine-6-phosphate|''N''-acetyl-glucosamine-6-phosphate]]. This reaction is [[EC 5.4.2.10]], catalyzed by GlmM. [33] => # {{anchor|GlmU}}In step three of the synthesis process, the ''N''-acetyl-glucosamine-6-phosphate is isomerized, which will change ''N''-acetyl-glucosamine-6-phosphate to [[N-acetyl-glucosamine-1-phosphate|''N''-acetyl-glucosamine-1-phosphate]]. This is [[EC 2.3.1.157]], catalyzed by GlmU. [34] => # In step 4, the ''N''-acetyl-glucosamine-1-phosphate, which is now a monophosphate, attacks [[Uridine triphosphate|UTP]]. Uridine triphosphate, which is a [[pyrimidine]] [[nucleotide]], has the ability to act as an energy source. In this particular reaction, after the monophosphate has attacked the UTP, an inorganic pyrophosphate is given off and is replaced by the monophosphate, creating UDP-N-acetylglucosamine (2,4). (When [[Uridine diphosphate|UDP]] is used as an energy source, it gives off an inorganic phosphate.) This initial stage, is used to create the precursor for the NAG in peptidoglycan. This is [[EC 2.7.7.23]], also catalyzed by GlmU, which is a bifunctional enzyme. [35] => # 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 [[Phosphoenolpyruvic acid|phosphoenolpyruvate]]. This creates what is called an enol derivative. [[EC 2.5.1.7]], catalyzed by MurA. [36] => # In step 6, the enol is reduced to a "lactyl moiety" by NADPH in step six. [[EC 1.3.1.98]], catalyzed by MurB. [37] => # 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. This is a string of three reactions: [[EC 6.3.2.8]] by MurC, [[EC 6.3.2.9]] by MurD, and [[EC 6.3.2.13]] by MurE. [38] => [39] => Each of these reactions requires the energy source ATP. This is all referred to as Stage one. [40] => [41] => 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. [42] => # [[Undecaprenyl phosphate]] will attack the UDP-MurNAc penta, creating a PP-MurNac penta, which is now a lipid ([[lipid I]]). [[EC 2.7.8.13]] by MraY. [43] => # UDP-GlcNAc is then transported to MurNAc, creating Lipid-PP-MurNAc penta-GlcNAc ([[lipid II]]), a disaccharide, also a precursor to peptidoglycan. [[EC 2.4.1.227]] by MurG. [44] => # Lipid II is transported across the membrane by [[flippase]] (MurJ), a discovery made in 2014 after decades of searching.{{cite journal | vauthors = Sham LT, Butler EK, Lebar MD, Kahne D, Bernhardt TG, Ruiz N | title = Bacterial cell wall. MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis | journal = Science | volume = 345 | issue = 6193 | pages = 220–222 | date = July 2014 | pmid = 25013077 | pmc = 4163187 | doi = 10.1126/science.1254522 | bibcode = 2014Sci...345..220S }} 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.{{cite book | vauthors = White D |year=2007 |title=The physiology and biochemistry of prokaryotes |edition=3rd |location=NY |publisher=Oxford University Press Inc.}} [45] => # In a final step, the [[DD-transpeptidase]] (TPase, EC 3.4.16.4) crosslinks individual glycan chains. This protein is also known as the [[penicillin-binding protein]]. Some versions of the enzyme also performs the glycosyltransferase function, while others leave the job to a separate enzyme. [46] => {{clear left}} [47] => [48] => == Pseudopeptidoglycan == [49] => {{main|Pseudopeptidoglycan}} [50] => In some [[archaea]], i.e. members of the [[Methanobacteriales]] and in the genus ''[[Methanopyrus]]'', [[pseudopeptidoglycan]] (pseudomurein) has been found. In pseudopeptidoglycan the sugar residues are β-(1,3) linked ''N''-acetylglucosamine and [[N-Acetyltalosaminuronic acid|''N''-acetyltalosaminuronic acid]]. This makes the cell walls of such archaea insensitive to [[lysozyme]].{{cite book | vauthors = Madigan MT, Martinko JM, Dunlap PV, Clark DP | title = Brock Biology of Microorganisms | edition = 12th | location = San Francisco, CA | publisher = Pearson/Benjamin Cummings | date = 2009 }} The biosynthesis of pseudopeptidoglycan has been described.{{cite journal | vauthors = König H, Kandler O, Hammes W | title = Biosynthesis of pseudomurein: isolation of putative precursors from Methanobacterium thermoautotrophicum | journal = Canadian Journal of Microbiology | volume = 35 | issue = 1 | pages = 176–181 | date = January 1989 | pmid = 2720492 | doi = 10.1139/m89-027 | author-link2 = Otto Kandler }} [51] => [52] => == Recognition by immune system == [53] => Peptidoglycan recognition is an evolutionarily conserved process.{{cite journal | vauthors = Wolf AJ, Underhill DM | title = Peptidoglycan recognition by the innate immune system | journal = Nature Reviews. Immunology | volume = 18 | issue = 4 | pages = 243–254 | date = April 2018 | pmid = 29292393 | doi = 10.1038/nri.2017.136 | s2cid = 3894187 }} 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).{{cite journal | vauthors = Bersch KL, DeMeester KE, Zagani R, Chen S, Wodzanowski KA, Liu S, Mashayekh S, Reinecker HC, Grimes CL | display-authors = 6 | title = Bacterial Peptidoglycan Fragments Differentially Regulate Innate Immune Signaling | journal = ACS Central Science | volume = 7 | issue = 4 | pages = 688–696 | date = April 2021 | pmid = 34056099 | pmc = 8155477 | doi = 10.1021/acscentsci.1c00200 }} The aim of these modifications is to alter the properties of the cell wall, which plays a vital role in [[pathogenesis]]. [54] => [55] => Peptidoglycans can be degraded by several enzymes ([[lysozyme]], glucosaminidase, [[endopeptidase]]...), producing immunostimulatory fragments (sometimes called muropeptides{{cite journal | vauthors = Bastos PA, Wheeler R, Boneca IG | title = Uptake, recognition and responses to peptidoglycan in the mammalian host | journal = FEMS Microbiology Reviews | volume = 45 | issue = 1 | pages = fuaa044 | date = January 2021 | pmid = 32897324 | pmc = 7794044 | doi = 10.1093/femsre/fuaa044 }}) that are critical for mediating [[Host–pathogen interaction|host-pathogen interactions]]. These include MDP ([[muramyl dipeptide]]), NAG ([[N-Acetylglucosamine|N-acetylglucosamine]]) or iE-DAP (γ-d-glutamyl-meso-diaminopimelic acid). [56] => [57] => Peptidoglycan from [[Gut microbiota|intestinal bacteria]] (both pathogens and commensals) crosses the intestinal barrier even under physiological conditions. 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 vesicle trafficking|membrane vesicles]]) or host cell-mediated (receptor-mediated, peptide transporters). [[Bacterial secretion system]]s are protein complexes used for the delivery of virulence factors across the bacterial cell envelope to the exterior environment.{{cite journal | vauthors = Sun Q, Liu X, Li X | title = Peptidoglycan-based immunomodulation | journal = Applied Microbiology and Biotechnology | volume = 106 | issue = 3 | pages = 981–993 | date = February 2022 | pmid = 35076738 | doi = 10.1007/s00253-022-11795-4 | s2cid = 246276803 }} Intracellular bacterial pathogens invade eukaryotic cells (which may lead to the formation of [[phagolysosome]]s and/or [[autophagy]] activation), or bacteria may be engulfed by [[phagocyte]]s ([[macrophage]]s, [[monocyte]]s, [[neutrophil]]s...). The bacteria-containing [[phagosome]] may then fuse with [[endosome]]s and [[lysosome]]s, leading to degradation of bacteria and generation of polymeric peptidoglycan fragments and muropeptides. [58] => [59] => === Receptors === [60] => [[Innate immune system]] senses intact peptidoglycan and peptidoglycan fragments using numerous PRRs ([[pattern recognition receptor]]s) that are secreted, expressed intracellularly or expressed on the cell surface. [61] => [62] => ==== Peptidoglycan recognition proteins ==== [63] => [[Peptidoglycan recognition protein|PGLYRPs]] are conserved from [[insect]]s to [[mammal]]s. Mammals produce four secreted soluble peptidoglycan recognition proteins ([[Peptidoglycan recognition protein 1|PGLYRP-1]], [[Peptidoglycan recognition protein 2|PGLYRP-2]], [[Peptidoglycan recognition protein 3|PGLYRP-3]] and [[Peptidoglycan recognition protein 4|PGLYRP-4]]) that recognize muramyl pentapeptide or tetrapeptide. They can also bind to [[Lipopolysaccharide|LPS]] and other molecules by using binding sites outside of the peptidoglycan-binding groove. 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). [64] => [65] => Each of the mammalian PGLYRPs display unique tissue expression patterns. PGLYRP-1 is mainly expressed in the granules of [[neutrophil]]s and [[eosinophil]]s. PGLYRP-3 and 4 are expressed by several tissues such as skin, sweat glands, eyes or the intestinal tract. PGLYRP-1, 3 and 4 form disulphide-linked [[homodimers]] and [[heterodimers]] essential for their bactericidal activity. Their binding to bacterial cell wall peptidoglycans can induce bacterial cell death by interaction with various bacterial transcriptional regulatory proteins. PGLYRPs are likely to assist in bacterial killing by cooperating with other PRRs to enhance recognition of bacteria by phagocytes. [66] => [67] => PGLYRP-2 is primarily expressed by the [[liver]] and secreted into the circulation. Also, its expression can be induced in skin [[keratinocyte]]s, oral and intestinal [[Epithelium|epithelial]] cells. In contrast with the other PGLYRPs, PGLYRP-2 has no direct bactericidal activity. It possesses peptidoglycan amidase activity, it hydrolyses the lactyl-amide bond between the [[MurNAc]] and the first amino acid of the stem peptide of peptidoglycan. It is proposed, that the function of PGLYRP-2 is to prevent over-activation of the immune system and [[inflammation]]-induced tissue damage in response to [[NOD2]] ligands (see below), as these muropeptides can no longer be recognized by NOD2 upon separation of the peptide component from MurNAc. Growing evidence suggests that peptidoglycan recognition protein family members play a dominant role in the [[Tolerance to infections|tolerance]] of intestinal epithelial cells toward the commensal microbiota.{{cite journal | vauthors = Liang Y, Yang L, Wang Y, Tang T, Liu F, Zhang F | title = Peptidoglycan recognition protein SC (PGRP-SC) shapes gut microbiota richness, diversity and composition by modulating immunity in the house fly Musca domestica | journal = Insect Molecular Biology | pages = 200–212 | date = December 2022 | volume = 32 | issue = 2 | pmid = 36522831 | doi = 10.1111/imb.12824 | s2cid = 254807823 }} It has been demonstrated that expression of PGLYRP-2 and 4 can influence the composition of the intestinal [[microbiota]]. [68] => [69] => Recently, it has been discovered, that PGLYRPs (and also NOD-like receptors and peptidoglycan transporters) are highly expressed in the developing mouse [[brain]].{{cite journal | vauthors = Gonzalez-Santana A, Diaz Heijtz R | title = Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior | journal = Trends in Molecular Medicine | volume = 26 | issue = 8 | pages = 729–743 | date = August 2020 | pmid = 32507655 | doi = 10.1016/j.molmed.2020.05.003 | s2cid = 219539658 | url = https://hal.archives-ouvertes.fr/hal-03492013/file/S1471491420301325.pdf }} PGLYRP-2 and is highly expressed in [[neuron]]s 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. [70] => [71] => ==== NOD-like receptors ==== [72] => Probably the most well-known receptors of peptidoglycan are the [[NOD-like receptor]]s (NLRs), mainly [[NOD1]] and [[NOD2]]. The NOD1 receptor is activated after iE-DAP (γ-d-glutamyl-meso-diaminopimelic acid) binding, while NOD2 recognizes MDP (muramyl dipeptide), by their [[LRR domain]]s. Activation leads to self-oligomerization, resulting in activation of two signalling cascades. One triggers activation of [[NF-κB]] (through RIP2, [[MAP3K7|TAK1]] and [[IκB kinase|IKK]]{{Cite book | vauthors = Murphy K, Weaver C, Janeway C |title=Janeway's immunobiology |year=2017 |isbn=978-0-8153-4505-3 |edition=9th |location=New York |publisher=Garland Science |pages=45, 96–98 |oclc=933586700}}), second leads to [[Mitogen-activated protein kinase|MAPK]] signalling cascade. Activation of these pathways induces production of inflammatory [[cytokine]]s and [[chemokine]]s. [73] => [74] => NOD1 is expressed by diverse cell types, including myeloid phagocytes, epithelial cells and neurons. NOD2 is expressed in monocytes and macrophages, epithelial intestinal cells, [[Paneth cell]]s, [[dendritic cell]]s, [[osteoblast]]s, keratinocytes and other epithelial cell types. As [[cytosol]]ic 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. [75] => [76] => Recently, it was demonstrated that [[NLRP3]] is activated by peptidoglycan, through a mechanism that is independent of NOD1 and NOD2. In macrophages, N-acetylglucosamine generated by peptidoglycan degradation was found to inhibit hexokinase activity and induce its release from the [[Mitochondrion|mitochondrial]] [[membrane]]. It promotes NLRP3 [[inflammasome]] activation through a mechanism triggered by increased mitochondrial membrane permeability. [77] => [78] => [[NLRP1]] is also considered as a cytoplasmic sensor of peptidoglycan. It can sense MDP and promote [[Interleukin-1 family|IL-1]] secretion through binding NOD2. [79] => [80] => ==== C-type lectin receptors (CLRs) ==== [81] => [[C-type lectin]]s are a diverse superfamily of mainly Ca2+-dependent proteins that bind a variety of [[carbohydrate]]s (including the glycan skeleton of peptidoglycan), and function as innate immune receptors. CLR proteins that bind to peptidoglycan include MBL ([[Mannose-Binding Lectin|mannose binding lectin]]), [[ficolin]]s, [[REG3A|Reg3A]] (regeneration gene family protein 3A) and PTCLec1. In mammals, they initiate the [[Lectin pathway|lectin-pathway]] of the [[Complement system|complement]] cascade. [82] => [83] => ==== Toll-like receptors ==== [84] => The role of [[Toll-like receptor|TLRs]] in direct recognition of peptidoglycan is controversial. In some studies, has been reported that peptidoglycan is sensed by [[Toll-like receptor 2|TLR2]].{{cite journal | vauthors = Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D | title = Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2 | journal = Journal of Immunology | volume = 163 | issue = 1 | pages = 1–5 | date = July 1999 | doi = 10.4049/jimmunol.163.1.1 | pmid = 10384090 | s2cid = 23630870 | doi-access = free }} But this TLR2-inducing activity could be due to cell wall [[lipoprotein]]s and [[lipoteichoic acid]]s 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. [85] => [86] => == As vaccine or adjuvant == [87] => Peptidoglycan is immunologically active, which can stimulate immune cells to increase the expression of cytokines and enhance antibody-dependent specific response when combined with [[vaccine]] or as [[Adjuvants, immunologic|adjuvant]] alone. MDP, which is the basic unit of peptidoglycan, was initially used as the active component of [[Freund's adjuvant]]. Peptidoglycan from ''[[Staphylococcus aureus]]'' was used as a vaccine to protect mice, showing that after vaccine injection for 40 weeks, the mice survived from ''S. aureus'' challenge at an increased [[lethal dose]].{{cite journal | vauthors = Capparelli R, Nocerino N, Medaglia C, Blaiotta G, Bonelli P, Iannelli D | title = The Staphylococcus aureus peptidoglycan protects mice against the pathogen and eradicates experimentally induced infection | journal = PLOS ONE | volume = 6 | issue = 12 | pages = e28377 | date = 2011-12-01 | pmid = 22145040 | pmc = 3228750 | doi = 10.1371/journal.pone.0028377 | bibcode = 2011PLoSO...628377C | veditors = Cardona PJ | doi-access = free }} [88] => [89] => == Inhibition and degradation == [90] => Some [[Antibiotics|antibacterial drugs]] such as [[penicillin]] interfere with the production of peptidoglycan by binding to bacterial enzymes known as [[penicillin-binding proteins]] or [[DD-transpeptidase]]s. Penicillin-binding proteins form the bonds between oligopeptide crosslinks in peptidoglycan. For a bacterial cell to reproduce through [[binary fission]], more than a million peptidoglycan subunits (NAM-NAG+oligopeptide) must be attached to existing subunits.{{cite book |author=Bauman R |title=Microbiology with Diseases by Taxonomy |publisher=Benjamin Cummings |year=2007 |isbn=978-0-8053-7679-1 |edition=2nd}} Mutations in genes coding for transpeptidases that lead to reduced interactions with an antibiotic are a significant source of emerging [[antibiotic resistance]].{{cite journal | vauthors = Spratt BG | title = Resistance to antibiotics mediated by target alterations | journal = Science | volume = 264 | issue = 5157 | pages = 388–393 | date = April 1994 | pmid = 8153626 | doi = 10.1126/science.8153626 | bibcode = 1994Sci...264..388S | s2cid = 30578841 }} Since peptidoglycan is also lacking in L-form bacteria and in mycoplasmas, both are resistant against penicillin. [91] => [92] => 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.{{cite journal | vauthors = Sarkar P, Yarlagadda V, Ghosh C, Haldar J | title = A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics | journal = MedChemComm | volume = 8 | issue = 3 | pages = 516–533 | date = March 2017 | pmid = 30108769 | pmc = 6072328 | doi = 10.1039/c6md00585c }} [93] => [94] => [[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 [[Lipopolysaccharide|LPS]] covering the peptidoglycan layer. Several bacterial peptidoglycan modifications can result in resistance to degradation by lysozyme. Susceptibility of bacteria to degradation is also considerably affected by exposure to [[antibiotic]]s. Exposed bacteria synthesize peptidoglycan that contains shorter sugar chains that are poorly crosslinked and this peptidoglycan is then more easily degraded by lysozyme. [95] => [96] => == See also == [97] => * [[Undecaprenyl-diphosphatase]] [98] => [99] => == References == [100] => {{Reflist}} [101] => [102] => == External links == [103] => * [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.figgrp.298 Diagrammatic representation of peptidoglycan structures.] [104] => * [http://pubs.acs.org/doi/abs/10.1021/bi4010446 Structure of MurNAc 6-Phosphate Hydrolase (MurQ) from Haemophilus influenzae with a Bound Inhibitor.] [105] => {{Mucoproteins}} [106] => {{Bacteria}} [107] => [108] => [[Category:Membrane biology]] [109] => [[Category:Glycobiology]] [] => )
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Peptidoglycan

Peptidoglycan, also known as murein, is a complex, rigid structure that forms the cell walls of bacteria. It is composed of long carbohydrate chains, known as glycan strands, which are cross-linked by short peptide chains.

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It is composed of long carbohydrate chains, known as glycan strands, which are cross-linked by short peptide chains. Peptidoglycan provides structural support to bacterial cells, protecting them from external stressors, and plays a crucial role in cell division and bacterial growth. It is also a target for many antibiotics, as disrupting peptidoglycan synthesis can weaken or kill bacteria. This Wikipedia page provides an in-depth explanation of the composition, structure, function, biosynthesis, and importance of peptidoglycan in bacterial physiology. It also discusses the various enzymes and proteins involved in peptidoglycan metabolism and provides examples of bacterial species that have unique variations in their peptidoglycan composition.

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