The Total Synthesis of Lipid I

VanNieuwenhze, Michael S.; Mauldin, Scott C.; Zia‐Ebrahimi, Mohammad; Aikins, James; Blaszczak, Larry C.

doi:10.1021/ja016082o

Cited by 50 publications

(49 citation statements)

References 37 publications

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“…Because they are present naturally in very low abundance, it was not feasible to isolate them from bacterial cells in useful quantities (van Heijenoort et al , 1992; Guan et al , 2005). Chemical syntheses were published for lipid I (VanNieuwenhze et al , 2001) and for lipid II (Ye et al , 2001; VanNieuwenhze et al , 2002), however the synthetic routes were long and proceeded in fairly low overall yield. Auger et al , (1997, 2003) first succeeded for the hemi‐synthesis of functional analogues of both lipids I and II.…”

Section: Chemical and Enzymatic Synthesis Of Lipids I And Ii And Analmentioning

confidence: 99%

The biosynthesis of peptidoglycan lipid-linked intermediates

et al. 2008

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The biosynthesis of bacterial cell wall peptidoglycan is a complex process involving many different steps taking place in the cytoplasm (synthesis of the nucleotide precursors) and on the inner and outer sides of the cytoplasmic membrane (assembly and polymerization of the disaccharide-peptide monomer unit, respectively). This review summarizes the current knowledge on the membrane steps leading to the formation of the lipid II intermediate, i.e. the substrate of the polymerization reactions. It makes the point on past and recent data that have significantly contributed to the understanding of the biosynthesis of undecaprenyl phosphate, the carrier lipid required for the anchoring of the peptidoglycan hydrophilic units in the membrane, and to the characterization of the MraY and MurG enzymes which catalyze the successive transfers of the N-acetylmuramoyl-peptide and N-acetylglucosamine moieties onto the carrier lipid, respectively. Enzyme inhibitors and antibacterial compounds interfering with these essential metabolic steps and interesting targets are presented.

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Section: Chemical and Enzymatic Synthesis Of Lipids I And Ii And Analmentioning

confidence: 99%

The biosynthesis of peptidoglycan lipid-linked intermediates

et al. 2008

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“…The characterization of several GT enzymes has been made possible thanks to the development of methods for the synthesis or isolation of labeled (fluorescent or radioactive) lipid II and lipid IV (lipid-linked tetrasaccharide) substrates and analogs (Schwartz et al, 2001; VanNieuwenhze et al, 2001, 2002; Ye et al, 2001; Breukink et al, 2003; Zhang et al, 2007; Gampe et al, 2011; Shih et al, 2011). This has allowed the development of assays to estimate their activity, such as the continuous fluorescent assay (Schwartz et al, 2002), which could be adapted to a microtiter plate format to screen for assay conditions and GT inhibitors (Offant et al, 2010; Derouaux et al, 2011).…”

Section: The Glycosyltransferases: Substrates Structure and Mechanismmentioning

confidence: 99%

Peptidoglycan Glycosyltransferase Substrate Mimics as Templates for the Design of New Antibacterial Drugs

Derouaux¹,

Sauvage²,

Terrak³

2013

Front. Immunol.

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Peptidoglycan (PG) is an essential net-like macromolecule that surrounds bacteria, gives them their shape, and protects them against their own high osmotic pressure. PG synthesis inhibition leads to bacterial cell lysis, making it an important target for many antibiotics. The final two reactions in PG synthesis are performed by penicillin-binding proteins (PBPs). Their glycosyltransferase (GT) activity uses the lipid II precursor to synthesize glycan chains and their transpeptidase (TP) activity catalyzes the cross-linking of two glycan chains via the peptide side chains. Inhibition of either of these two reactions leads to bacterial cell death. β-lactam antibiotics target the transpeptidation reaction while antibiotic therapy based on inhibition of the GTs remains to be developed. Ongoing research is trying to fill this gap by studying the interactions of GTs with inhibitors and substrate mimics and utilizing the latter as templates for the design of new antibiotics. In this review we present an updated overview on the GTs and describe the structure-activity relationship of recently developed synthetic ligands.

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“…Furthermore, citronellyllipid I analogues containing ␣-D-N-acetylglucosaminyl, ␣-Dglucosyl, and ␣-D-N-acetylmuramyl carbohydrates were made (47). At the same time, two chemical syntheses of natural lysine-containing lipid I were reported (183,197). They involved the coupling of protected phospho-N-acetylmuramoylpentapeptide to undecaprenyl monophosphate by application of the 1,1Ј-carbonyldiimidazole (197) or the phosphoroimidazolidate (183) method.…”

Section: Synthesis Of the Lipid Intermediates And Analoguesmentioning

confidence: 99%

Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan

Heijenoort

2007

Microbiol Mol Biol Rev

172

135

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SUMMARY This review is an attempt to bring together and critically evaluate the now-abundant but dispersed data concerning the lipid intermediates of the biosynthesis of bacterial peptidoglycan. Lipid I, lipid II, and their modified forms play a key role not only as the specific link between the intracellular synthesis of the peptidoglycan monomer unit and the extracytoplasmic polymerization reactions but also in the attachment of proteins to the bacterial cell wall and in the mechanisms of action of antibiotics with which they form specific complexes. The survey deals first with their detection, purification, structure, and preparation by chemical and enzymatic methods. The recent important advances in the study of transferases MraY and MurG, responsible for the formation of lipids I and II, are reported. Various modifications undergone by lipids I and II are described, especially those occurring in gram-positive organisms. The following section concerns the cellular location of the lipid intermediates and the translocation of lipid II across the cytoplasmic membrane. The great efforts made since 2000 in the study of the glycosyltransferases catalyzing the glycan chain formation with lipid II or analogues are analyzed in detail. Finally, examples of antibiotics forming complexes with the lipid intermediates are presented.

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The Total Synthesis of Lipid I

Cited by 50 publications

References 37 publications

The biosynthesis of peptidoglycan lipid-linked intermediates

The biosynthesis of peptidoglycan lipid-linked intermediates

Peptidoglycan Glycosyltransferase Substrate Mimics as Templates for the Design of New Antibacterial Drugs

Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan

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