Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...

, which is

amphipathic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...

and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several

antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...

. A number of analogous compounds are produced via a similar pathway in some bacteria, giving rise to cell wall modifications. See EC 2.4.1.227 for more information.

Synthesis

In peptidoglycan biosynthetic pathway

Lipid II is the final intermediate in

peptidoglycan synthesis Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid Cell wall#Bacterial_cell_walls, cell wall (murein sac ...

. It is formed when the MurG transferase catalyzes addition of ''N''-acetylglucosamine (GlcNAc) to Lipid I, resulting in a complete disaccharide-pentapeptide monomer with a bactoprenol-pyrophosphate anchor. This occurs on the inside of the cytoplasmic membrane, where the bactoprenol chain is embedded in the inner leaflet of the bilayer. Lipid II is then transported across the membrane by a

flippase Flippases (rarely spelled flipases) are transmembrane lipid transporter proteins located in the membrane which belong to ABC transporter or P4-type ATPase families. They are responsible for aiding the movement of phospholipid molecules between th ...

, to expose the disaccharide-pentapeptide monomer, which is the pentapeptide stem consisting of L-Ala-γ-D-Glu-m-DAP-D-Ala-D-Ala between GlcNAc and ''N''-acetylmuramic acid (MurNAc), for polymerization and cross-linking into peptidoglycan. The remaining bactoprenol-pyrophosphate is then recycled to the interior of the membrane. Lipid II has been referred to as the "shuttle carrier" of peptidoglycan "building blocks'. The essential MurJ

that translocates lipid II across the cytoplasmic membrane was only published in July 2014, after decades of searching. The discovery remains somewhat controversial as assay results are conflicting; FtsW ( EC 2.4.1.129) was proposed as an alternative, with evidence strongly favoring the MurJ side since 2019.

Artificial production

A method for artificial production of lipid II has been described. For synthesis of lipid II from UDP-MurNAc pentapeptide and undecaprenol, the enzymes MraY, MurG, and undecaprenol kinase can be used. Synthetic Lipid II analogues are used in experiments studying how it interacts with and binds molecules. Significant quantities of the important peptidoglycan precursor have also be isolated, following accumulation in bacterial cells.

Functions

Polymers of lipid II form a linear glycan chain. This reaction is catalyzed by the

glycosyltransferase Glycosyltransferases (GTFs, Gtfs) are enzymes (EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the "glycosyl donor") to a nucleophilic glyco ...

s of family 51 (GT51). Transpeptidases cross link the chains and form a net-like peptidoglycan macromolecule. The resulting glycopeptide is an essential part of the envelope of many bacteria. Lipid II was estimated to exist at a concentration of less than 2000 molecules per bacterial cell. Lipid II biosynthesis is functional and essential even in organisms without a cell wall like ''Chlamydia'' and ''

Wolbachia ''Wolbachia'' is a genus of intracellular bacteria that infects mainly arthropod species, including a high proportion of insects, and also some nematodes. It is one of the most common parasitic microbes, and is possibly the most common reproducti ...

''. It has been hypothesized that maintaining lipid II biosynthesis reflects its role in prokaryotic

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...

. In the discovery and mechanism of assembly of pili in gram positive bacteria Lipid II has been implicated as a crucial structural molecule. It anchors the pili during or after polymerization of the pilus components.Pili in Gram-positive pathogens, Nature, vol 4, pg 513

Antibiotics

Since Lipid II must be flipped outside the cytoplasmic membrane before incorporation of its disaccharide-peptide unit into peptidoglycan, it is a relatively accessible target for antibiotics. These antibiotics fight bacteria by either directly inhibiting the peptidoglycan synthesis, or by binding to lipid II to form destructive pores in the cytoplasmic membrane. Examples of antibiotics that target Lipid II include: *

Vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

and its synthetic derivatives * Ramoplanin *Several

lantibiotics Lantibiotics are a class of polycyclic peptide antibiotics that contain the characteristic thioether amino acids lanthionine or methyllanthionine, as well as the Saturated and unsaturated compounds, unsaturated amino acids dehydroalanine, and 2-Am ...

, including the common food preservative

nisin Nisin is a polycyclic antibacterial peptide produced by the bacterium ''Lactococcus lactis'' that is used as a food preservative. It has 34 amino acid residues, including the uncommon amino acids lanthionine (Lan), methyllanthionine (MeLan), di ...

Teixobactin Teixobactin () is a depsipeptide, peptide-like secondary metabolite of some species of bacteria, that kills some gram-positive bacteria. It appears to belong to a new Antibiotic classes, class of antibiotics, and harms bacteria by binding to lipid ...

* Copsin *Human alpha defensins

Binding

The D-Ala-D-Ala terminus is used by

glycopeptide Glycopeptides are peptides that contain carbohydrate moieties ( glycans) covalently attached to the side chains of the amino acid residues that constitute the peptide. Over the past few decades it has been recognised that glycans on cell surfa ...

antibiotic

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

to inhibit lipid I- and lipid II-consuming peptidoglycan synthesis; in vancomycin-resistant strains vancomycin cannot bind, because a crucial hydrogen bond is lost. Oritavancin also uses the D-Ala-D-Ala terminus, but in addition it uses the crossbridge and D-iso-glutamine in position 2 of the lipid II stem peptide, as present in a number of Gram-positive pathogens, like staphylococci and

enterococci ''Enterococcus'' is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococci) or short chains, and are difficult to distinguish from streptococci on physical charac ...

. The increased binding of oritavancin through amidation of lipid II can compensate for the loss of a crucial hydrogen bond in vancomycin-resistant strains, Lantibiotics recognize lipid-II by its

pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...

. Lipid II interacts with human alpha defensins, a class of

antimicrobial peptide Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...

s, such as Defensin, alpha 1. The latter has been used to describe and predict binding of synthetic low-molecular weight compounds created as possible therapeutic agents in treating of Gram-positive infections.

Penicillin-binding protein 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 discov ...

4 exchanges d-amino acids into Lipid II (and Lipid I), acting as a transpeptidase in vitro.

References

External links

* {{MeshName, Lipid+II Lipids Cell anatomy