Lipid II

Last updated
Lipid II
Lipid II structure.svg
Names
Systematic IUPAC name
(2R,5R,8S,13R,16S,19R)-19-{[(2R,3R,4R,5S,6R)-3-Acetamido-5-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-2-[(1,3-dihydroxy-1,3-dioxo-3-{[(2Z,6Z,10Z,14Z,18Z,22Z,26Z,30Z,34E,38E,42E)-3,7,11,15,19,23,27,31,35,39,43-undecamethyltetratetraconta-2,6,10,14,18,22,26,30,34,38,42-undecaen-1-yl]oxy}-1λ5,3λ5-diphosphoxan-1-yl)oxy]-6-(hydroxymethyl)oxan-4-yl]oxy}-8-(4-aminobutyl)-13-carboxy-2,5,16-trimethyl-4,7,10,15,18-pentaoxo-3,6,9,14,17-pentaazaicosan-1-oic acid
Identifiers
3D model (JSmol)
9039417
ChEBI
ChemSpider
KEGG
PubChem CID
  • InChI=1S/C94H156N8O26P2/c1-59(2)31-21-32-60(3)33-22-34-61(4)35-23-36-62(5)37-24-38-63(6)39-25-40-64(7)41-26-42-65(8)43-27-44-66(9)45-28-46-67(10)47-29-48-68(11)49-30-50-69(12)54-56-122-129(118,119)128-130(120,121)127-94-82(100-75(18)106)86(85(79(58-104)125-94)126-93-81(99-74(17)105)84(109)83(108)78(57-103)124-93)123-73(16)89(112)96-71(14)88(111)102-77(92(116)117)52-53-80(107)101-76(51-19-20-55-95)90(113)97-70(13)87(110)98-72(15)91(114)115/h31,33,35,37,39,41,43,45,47,49,54,70-73,76-79,81-86,93-94,103-104,108-109H,19-30,32,34,36,38,40,42,44,46,48,50-53,55-58,95H2,1-18H3,(H,96,112)(H,97,113)(H,98,110)(H,99,105)(H,100,106)(H,101,107)(H,102,111)(H,114,115)(H,116,117)(H,118,119)(H,120,121)/b60-33+,61-35+,62-37-,63-39-,64-41-,65-43-,66-45-,67-47-,68-49-,69-54-/t70-,71+,72-,73-,76+,77-,78-,79-,81-,82-,83-,84-,85-,86-,93+,94-/m1/s1 Yes check.svgY
    Key: ULXTYUPMJXVUHQ-OVTFQNCVSA-N Yes check.svgY
  • CC(C(=O)NC(CCC(=O)NC(CCCCN)C(=O)NC(C)C(=O)NC(C)C(=O)O)C(=O)O)NC(=O)C(C)OC1C(C(OC(C1OC2C(C(C(C(O2)CO)O)O)NC(=O)C)CO)OP(=O)(O)OP(=O)(O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)NC(=O)C
Properties
C94H156N8O26P2
Molar mass 1876.23 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. 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.

Contents

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. [1]

Synthesis

In peptidoglycan biosynthetic pathway

Lipid II is the final intermediate in peptidoglycan synthesis. 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, 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'. [2]

The essential MurJ flippase that translocates lipid II across the cytoplasmic membrane was only published in July 2014, after decades of searching. [3] 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. [4]

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. [5] Synthetic Lipid II analogues are used in experiments studying how it interacts with and binds molecules. [6] Significant quantities of the important peptidoglycan precursor have also be isolated, following accumulation in bacterial cells. [7]

Functions

Polymers of lipid II form a linear glycan chain. This reaction is catalyzed by the glycosyltransferases 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. [8]

Lipid II biosynthesis is functional and essential even in organisms without a cell wall like Chlamydia and Wolbachia . It has been hypothesized that maintaining lipid II biosynthesis reflects its role in prokaryotic cell division. [9]

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. [10]

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. [11] Examples of antibiotics that target Lipid II include:

Binding

The D-Ala-D-Ala terminus is used by glycopeptide antibiotic vancomycin 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. The increased binding of oritavancin through amidation of lipid II can compensate for the loss of a crucial hydrogen bond in vancomycin-resistant strains, [14]

Lantibiotics recognize lipid-II by its pyrophosphate. [2]

Lipid II interacts with human alpha defensins, a class of antimicrobial peptides, 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. [15]

Penicillin-binding protein 4 exchanges d-amino acids into Lipid II (and Lipid I), acting as a transpeptidase in vitro. [16]


Related Research Articles

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.

Lantibiotics are a class of polycyclic peptide antibiotics that contain the characteristic thioether amino acids lanthionine or methyllanthionine, as well as the unsaturated amino acids dehydroalanine, and 2-aminoisobutyric acid. They belong to ribosomally synthesized and post-translationally modified peptides.

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in gram-negative bacteria. Using cryo-electron microscopy it has been found that a much smaller periplasmic space is also present in gram-positive bacteria, between cell wall and the plasma membrane. The periplasm may constitute up to 40% of the total cell volume of gram-negative bacteria, but is a much smaller percentage in gram-positive bacteria.

<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.

<i>N</i>-Acetylmuramic acid Chemical compound

N-Acetylmuramic acid is an organic compound with the chemical formula C
11H
19NO
8. It is a monomer of peptidoglycan in most bacterial cell walls, which is built from alternating units of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid, cross-linked by oligopeptides at the lactic acid residue of MurNAc.

<span class="mw-page-title-main">Glycopeptide antibiotic</span> Class of antibiotic drugs

Glycopeptide antibiotics are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin, corbomycin, complestatin and the antitumor antibiotic bleomycin. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.

<span class="mw-page-title-main">Pseudopeptidoglycan</span>

Pseudopeptidoglycan 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, which are linked by β-1,3-glycosidic bonds.

<span class="mw-page-title-main">Penicillin-binding proteins</span> Class of proteins

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.

<span class="mw-page-title-main">Oritavancin</span> Pharmaceutical drug

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

Peptidoglycan glycosyltransferase is an enzyme used in the biosynthesis of peptidoglycan. It transfers a disaccharide-peptide from a donor substrate to synthesize a glycan chain.

In enzymology, a phospho-N-acetylmuramoyl-pentapeptide-transferase is an enzyme that catalyzes the chemical reaction

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

Bactoprenol also known as dolichol-11 and C55-isoprenyl alcohol (C55-OH) is a lipid first identified in certain species of lactobacilli. It is a hydrophobic alcohol that plays a key role in the growth of cell walls (peptidoglycan) in Gram-positive bacteria.

The bacterial cell wall provides strength and rigidity to counteract internal osmotic pressure, and protection against the environment. The peptidoglycan layer gives the cell wall its strength, and helps maintain the overall shape of the cell. The basic peptidoglycan structure of both Gram-positive and Gram-negative bacteria comprises a sheet of glycan chains connected by short cross-linking polypeptides. Biosynthesis of peptidoglycan is a multi-step process comprising three main stages:

  1. formation of UDP-N-acetylmuramic acid (UDPMurNAc) from N-acetylglucosamine (GlcNAc).
  2. addition of a short polypeptide chain to the UDPMurNAc.
  3. addition of a second GlcNAc to the disaccharide-pentapeptide building block and transport of this unit through the cytoplasmic membrane and incorporation into the growing peptidoglycan layer.

Teixobactin is a peptide-like secondary metabolite of some species of bacteria, that kills some gram-positive bacteria. It appears to belong to a new class of antibiotics, and harms bacteria by binding to lipid II and lipid III, important precursor molecules for forming the cell wall.

Eleftheria terrae is a recently discovered Gram-negative bacterium. E. terrae is a temporary name for the organism, as it was only discovered in 2014 and is still undergoing scientific study. It was found to produce a previously unknown antibiotic named teixobactin. The discovery of E. terrae could represent a new age of antibiotics, as teixobactin is the first new antibiotic discovered since the synthetic era of the 1980s. Prior research has indicated that other uncultivable bacteria like E. terrae have potential in the development of new antimicrobial agents.

Copsin is a fungal defensin that acts as an antimicrobial polypeptide secreted from the inky cap mushroom, first reported at the end of 2014. The fungal defensin acts against gram positive bacteria.

The bacterial murein precursor exporter (MPE) family is a member of the cation diffusion facilitator (CDF) superfamily of membrane transporters. Members of the MPE family are found in a large variety of Gram-negative and Gram-positive bacteria and facilitate the translocation of lipid-linked murein precursors. A representative list of proteins belonging to the MPE family can be found in the Transporter Classification Database.

The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily is a group of integral membrane protein families. The MOP flippase superfamily includes twelve distantly related families, six for which functional data are available:

  1. One ubiquitous family (MATE) specific for drugs - (TC# 2.A.66.1) The Multi Antimicrobial Extrusion (MATE) Family
  2. One (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes - (TC# 2.A.66.2) The Polysaccharide Transport (PST) Family
  3. One (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes - (TC# 2.A.66.3) The Oligosaccharidyl-lipid Flippase (OLF) Family
  4. One (MVF) lipid-peptidoglycan precursor flippase involved in cell wall biosynthesis - (TC# 2.A.66.4) The Mouse Virulence Factor (MVF) Family
  5. One (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84 - (TC# 2.A.66.5) The Agrocin 84 Antibiotic Exporter (AgnG) Family
  6. And finally, one (Ank) that shuttles inorganic pyrophosphate (PPi) - (TC# 2.A.66.9) The Progressive Ankylosis (Ank) Family
<span class="mw-page-title-main">Peptidoglycan recognition protein 3</span>

Peptidoglycan recognition protein 3 is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP3 gene.

Undecaprenyl phosphate (UP), also known lipid-P, bactoprenol and C55-P., is a molecule with the primary function of trafficking polysaccharides across the cell membrane, largely contributing to the overall structure of the cell wall in Gram-positive bacteria. In some situations, UP can also be utilized to carry other cell-wall polysaccharides, but UP is the designated lipid carrier for peptidoglycan. During the process of carrying the peptidoglycan across the cell membrane, N-acetylglucosamine and N-acetylmuramic acid are linked to UP on the cytoplasmic side of the membrane before being carried across. UP works in a cycle of phosphorylation and dephosphorylation as the lipid carrier gets used, recycled, and reacts with undecaprenyl phosphate. This type of synthesis is referred to as de novo synthesis where a complex molecule is created from simpler molecules as opposed to a complete recycle of the entire structure.

References

  1. ↑ "MetaCyc EC 2.4.1.227". biocyc.org.
  2. 1 2 Anton Chugunov; Darya Pyrkova; Dmitry Nolde; Anton Polyansky; Vladimir Pentkovsky; Roman Efremov (Apr 16, 2013). "Lipid-II forms potential "landing terrain" for lantibiotics in simulated bacterial membrane". Sci. Rep. 3: 1678. Bibcode:2013NatSR...3E1678C. doi:10.1038/srep01678. PMC   3627190 . PMID   23588060.
  3. ↑ Lok-To Sham; Emily K. Butler; Matthew D. Lebar; et al. (11 July 2014). "MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis". Science. 345 (6193): 220–222. Bibcode:2014Sci...345..220S. doi:10.1126/science.1254522. PMC   4163187 . PMID   25013077.
  4. ↑ "TCDB 2.A.66.4.3". tcdb.org.
  5. ↑ Huang LY, Huang SH, Chang YC, Cheng WC, Cheng TJ, Wong CH (28 July 2014). "Enzymatic synthesis of lipid II and analogues". Angew Chem Int Ed Engl. 53 (31): 8060–5. doi:10.1002/anie.201402313. PMID   24990652.
  6. ↑ t Hart P, Oppedijk S, Breukink E, Martin NI (2016). "New Insights into Nisin's Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues". Biochemistry. 55 (1): 232–7. doi:10.1021/acs.biochem.5b01173. PMID   26653142.
  7. ↑ Qiao Y, Srisuknimit V, Rubino F, Schaefer K, Nuiz R, Walker S, Kahne D (2017). "Lipid II overproduction allows direct assay of transpeptidase inhibition by b-lactams". Nature Chemical Biology. 13 (7): 793–798. doi:10.1038/nchembio.2388. PMC   5478438 . PMID   28553948.
  8. ↑ Y. van Heijenoort; M. Gomez; M. Derrien; J. Ayala; J. van Heijenoort (1992). "Membrane intermediates in the peptidoglycan metabolism of Escherichia coli: possible roles of PBP 1b and PBP 3". J. Bacteriol. 174 (11): 3549–3557. doi:10.1128/jb.174.11.3549-3557.1992. PMC   206040 . PMID   1592809.
  9. ↑ Henrichfreise B, Schiefer A, Schneider T, et al. (September 2009). "Functional conservation of the lipid II biosynthesis pathway in the cell wall-less bacteria Chlamydia and Wolbachia: why is lipid II needed?". Mol Microbiol. 73 (5): 913–23. doi: 10.1111/j.1365-2958.2009.06815.x . PMID   19656295.
  10. ↑ Pili in Gram-positive pathogens, Nature, vol 4, pg 513
  11. 1 2 3 Heijenoort J (December 2007). "Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan". Microbiol Mol Biol Rev. 71 (4): 620–635. doi:10.1128/MMBR.00016-07. PMC   2168651 . PMID   18063720.
  12. ↑ de Kruijff B, van Dam V, Breukink E (12 November 2008). "Lipid II: A central component in bacterial cell wall synthesis and a target for antibiotics". Prostaglandins Leukot Essent Fatty Acids. 79 (3–5): 117–21. doi:10.1016/j.plefa.2008.09.020. hdl: 1874/33263 . PMID   19008088.
  13. ↑ Wright, Gerard (7 January 2015). "Antibiotics: An irresistible newcomer". Nature . 517 (7535): 442–444. Bibcode:2015Natur.517..442W. doi: 10.1038/nature14193 . PMID   25561172. S2CID   4464402.
  14. ↑ Münch D, Engels I, Müller A, Reder-Christ K, Falkenstein-Paul H, Bierbaum G, Grein F, Bendas G, Sahl HG, Schneider T (17 November 2014). "Structural variations of the cell wall precursor lipid II - Influence on binding and activity of the lipoglycopeptide antibiotic oritavancin". Antimicrobial Agents and Chemotherapy. 59 (2): 772–781. doi:10.1128/AAC.02663-14. PMC   4335874 . PMID   25403671.
  15. ↑ Varney KM, Bonvin AM, Pazgier M, et al. (2013). "Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II". PLOS Pathog. 9 (11): e1003732. doi: 10.1371/journal.ppat.1003732 . PMC   3820767 . PMID   24244161.
  16. ↑ Qiao Y, Lebar MD, Schirner K, Schaefer K, Tsukamoto H, Kahne D, Walker S (22 October 2014). "Detection of lipid-linked peptidoglycan precursors by exploiting an unexpected transpeptidase reaction". J Am Chem Soc. 136 (42): 14678–81. doi:10.1021/ja508147s. PMC   4210121 . PMID   25291014.
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