Pseudopeptidoglycan

Last updated February 02, 2024

Structure schematic, showing sugar units and UDP-L-Glu-g-L-Ala-e-L-Lys-L-Ala peptide stem. Additional glutamic acid residue attached to the L-Lys residue via a g bond not shown. Pseudopeptidoglycan.png — Structure schematic, showing sugar units and UDP-L-Glu-γ-L-Ala-ε-L-Lys-L-Ala peptide stem. Additional glutamic acid residue attached to the L-Lys residue via a γ bond not shown.

Pseudopeptidoglycan (also known as pseudomurein;^[2] PPG hereafter) is a major cell wall component of some Archaea that differs from bacterial peptidoglycan in chemical structure, but resembles bacterial peptidoglycan in function and physical structure. Pseudopeptidoglycan, in general, is only present in a few methanogenic archaea. The basic components are N-acetylglucosamine and N-acetyltalosaminuronic acid (bacterial peptidoglycan containing N-acetylmuramic acid instead), which are linked by β-1,3-glycosidic bonds.^[3]

Lysozyme, a host defense mechanism present in human secretions (e.g. saliva and tears) breaks β-1,4-glycosidic bonds to degrade peptidoglycan. However, because pseudopeptidoglycan has β-1,3-glycosidic bonds, lysozyme is ineffective. It was thought from these large differences in cell wall chemistry that archaeal cell walls and bacterial cell walls have not evolved from a common ancestor but are only the result of a convergent evolution,^[4] but recent structural work has revealed deeper homology.^[1]

No archaeal enzymes are known that cleave the β-1,3-glycosidic bonds in pseudopeptidoglycan, but it can be degraded by pseudomurein endoisopeptidase encoded by two prophages.^[5] The pseudomurein endoisopeptidases function by cleaving the peptide links between adjacent pseudopeptidoglycan strands.

Structure

Pseudopeptidoglycan is composed of two sugars, N-acetylglucosamine and N-acetyltalosaminuronic acid. These sugars are made of different amino acids, and the peptide cross-links within pseudopeptidoglycan are formed with different amino acids. The peptide bond is formed between the lysine of a N-acetyltalosaminuronic acid and a glutamine of a parallel N-acetyltalosaminuronic acid.^[6] Pseudopeptidoglycan, like peptidoglycan in bacteria, forms a mesh-like layer outside of the plasma membrane of the archaea.

Function

Only a few methanogenic archaea have cell walls composed of pseudopeptidoglycan. This component functions much like peptidoglycan in a bacterial cell.^[7] Pseudopeptidoglycan is used by the archaeal cell to determine its shape and provide structure to the cell. It is also used to protect the cell from undesired molecules or anything harmful in its environment.

Biosynthesis

PPG is produced by enzymes of two gene clusters. Recent work on the peptide ligases show, surprisingly, a common origin with murein synthesis. The pathway is now known to include the orthologous-to-bacteria CarB, MurC/D (peptide ligase), MurG, MraY, UppP, UppS, and flippase presumably performing an analogous function, and two novel but conserved transmembrane proteins. GlmM and GlmU, which produce UDP-GlcNAc in bacteria, are also present with phosphoglucomutase (PGM). Half of the species also have MurT and GatD, known to perform cell wall modifications in bacteria. No orthologous cross-linking enzymes have been identified. Notably, "formation of the disaccharide moiety of the glycopeptide monomer occurs before the transfer to membrane protein by MraY", as opposed to after in bacteria. Further work would be needed to connect these information into a coherent pathway.^[1]

Effects of different bacterial medicines on pseudopeptidoglycan

Lysozyme

Lysozyme is a natural defense mechanism in humans that has the ability to break down peptidoglycan in bacterial cells. It degrades the peptidoglycan by targeting the β-1,4-glycosidic bonds that connect the alternating amino sugars in which it is composed of.^[8] This degradation of the glycosidic bonds within peptidoglycan cause the sugars to separate and inhibit the structural integrity of the peptidoglycan and the bacteria.

Pseudopeptidoglycan, however, is composed of a different acidic amino sugar, which is N-acetyltalosaminuronic acid. This difference is the reason that it has β-1,3-glycosidic bonds (as opposed to the β-1,4-glycosidic bonds in bacteria).^[3] Lysozymes targets the linkage in peptidoglycan, and without that, becomes ineffective against pseudopeptidoglycan.

Penicillin

Penicillin is a group of antibiotics that have been effective against many bacterial infections. It attacks bacteria by targeting and inhibiting the transpeptidase that catalyzes the cross-linking of the amino sugars in peptidoglycan.^[9] However, pseudopeptidoglycan contains different amino sugars, and therefore, a different catalysis enzyme is used. The different amino acids cause antibiotics, that target cell walls like penicillin, to be ineffective against pseudopeptidoglycan.^[6]

Taxonomic distribution

PPG is found in the archaeal orders of Methanobacteriales and Methanopyrales.^[1] Some genera under these orders are:

Related Research Articles

A cell wall is a structural layer that surrounds some cell types, found immediately outside the cell membrane. It can be tough, flexible, and sometimes rigid. Primarily, it provides the cell with structural support, shape, protection, and functions as a selective barrier. Another vital role of the cell wall is to help the cell withstand osmotic pressure and mechanical stress. While absent in many eukaryotes, including animals, cell walls are prevalent in other organisms such as fungi, algae and plants, and are commonly found in most prokaryotes, with the exception of mollicute bacteria.

Penicillins are a group of β-lactam antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and 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. 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.

Autolysins are endogenous lytic enzymes that break down the peptidoglycan components of biological cells which enables the separation of daughter cells following cell division. They are involved in cell growth, cell wall metabolism, cell division and separation, as well as peptidoglycan turnover and have similar functions to lysozymes.

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<span class="mw-page-title-main">Lysozyme</span> Antimicrobial enzyme produced by animals

Lysozyme is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside hydrolase that catalyzes the following process:

<span class="mw-page-title-main">DD-transpeptidase</span> Bacterial enzyme

DD-transpeptidase is a bacterial enzyme that catalyzes the transfer of the R-L-αα-D-alanyl moiety of R-L-αα-D-alanyl-D-alanine carbonyl donors to the γ-OH of their active-site serine and from this to a final acceptor. It is involved in bacterial cell wall biosynthesis, namely, the transpeptidation that crosslinks the peptide side chains of peptidoglycan strands.

Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.

The bacterium, despite its simplicity, contains a well-developed cell structure which is responsible for some of its unique biological structures and pathogenicity. Many structural features are unique to bacteria and are not found among archaea or eukaryotes. Because of the simplicity of bacteria relative to larger organisms and the ease with which they can be manipulated experimentally, the cell structure of bacteria has been well studied, revealing many biochemical principles that have been subsequently applied to other organisms.

Lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages in order to cleave the host's cell wall during the final stage of the lytic cycle. Lysins are highly evolved enzymes that are able to target one of the five bonds in peptidoglycan (murein), the main component of bacterial cell walls, which allows the release of progeny virions from the lysed cell. Cell-wall-containing Archaea are also lysed by specialized pseudomurein-cleaving lysins, while most archaeal viruses employ alternative mechanisms. Similarly, not all bacteriophages synthesize lysins: some small single-stranded DNA and RNA phages produce membrane proteins that activate the host's autolytic mechanisms such as autolysins.

<span class="mw-page-title-main">Thienamycin</span> Chemical compound

Thienamycin is one of the most potent naturally produced antibiotics known thus far, discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes. Thienamycin is a zwitterion at pH 7.

Peptidoglycan recognition protein 2(PGLYRP2) is an enzyme, N-acetylmuramoyl-L-alanine amidase (NAMLAA), that hydrolyzes bacterial cell wall peptidoglycan and is encoded by the PGLYRP2 gene.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

Glucanases are enzymes that break down large polysaccharides via hydrolysis. The product of the hydrolysis reaction is called a glucan, a linear polysaccharide made of up to 1200 glucose monomers, held together with glycosidic bonds. Glucans are abundant in the endosperm cell walls of cereals such as barley, rye, sorghum, rice, and wheat. Glucanases are also referred to as lichenases, hydrolases, glycosidases, glycosyl hydrolases, and/or laminarinases. Many types of glucanases share similar amino acid sequences but vastly different substrates. Of the known endo-glucanases, 1,3-1,4-β-glucanase is considered the most active.

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References

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↑ Yocum, R. R.; Rasmussen, J. R.; Strominger, J. L. (1980-05-10). "The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase". The Journal of Biological Chemistry. 255 (9): 3977–3986. doi: 10.1016/S0021-9258(19)85621-1 . ISSN 0021-9258. PMID 7372662.