First Total Synthesis of the Re-Type Lipopolysaccharide

Yoshizaki, Hiroaki; Fukuda, Naohiro; Kenjiro, Sato; Oikawa, Masato; Fukase, Koichi; Suda, Yasuo; Kusumoto, Shoichi

doi:10.1002/1521-3773(20010417)40:8<1475::aid-anie1475>3.0.co;2-v

Cited by 108 publications

(73 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…-D-glucopyranoside (29). To a mixture of donor 27 (505 mg, 663 mmol), acceptor 28 (454 mg, 442 mmol) and MS4A (1.0 g) in anhydrous THF (15.0 mL) was added diethyl ether-boron trifluoride (1/1) (30.0 mL, 237 mmol) at 0 C under Ar atmosphere.…”

Section: -Propenyl 46-o-benzylidene-2-deoxy-2-(9-fluorenylmethoxycamentioning

confidence: 65%

See 1 more Smart Citation

Synthesis of Rubrivivax gelatinosus Lipid A and Analogues for Investigation of the Structural Basis for Immunostimulating and Inhibitory Activities

Fukase¹,

Fujimoto²,

Adachi³

et al. 2008

Bulletin of the Chemical Society of Japan

Self Cite

View full text Add to dashboard Cite

To elucidate the structural requirements for the endotoxic and antagonistic activities of lipid A derivatives, we have focused on the effects of the acyl moieties and acidic groups at the 1-and 4 0 -positions in the present study. We have synthesized new analogues corresponding to Rubrivivax gelatinosus lipid A, which has a characteristic symmetrical distribution of its acyl groups on its two glucosamine residues with shorter acyl groups (decanoyl groups (C 10 ) and lauryl groups (C 12 )) than Escherichia coli lipid A's. Carboxymethyl (CM) analogues in which one of the phosphates was replaced with a CM group were also synthesized with a different distribution of acyl groups. Biological tests revealed that the acyl group distribution in the lipid A analogue, strongly affected its bioactivity. The synthetic Ru. gelatinosus type lipid A showed potent antagonistic activity against LPS, whereas its 1-O-carboxymethyl analogue showed weak endotoxic activity. These results demonstrate that when lipid A has shorter (C 10 and C 12 ) hexa-acyl groups, its bioactivity is more easily affected by small structural differences, such as differences in acidic groups or acyl group distribution, and that they can change bioactivity from endotoxic to agonistic or vice versa at this structural boundary for the bioactivity.The innate immune system is a phylogenetically ancient defense mechanism conserved between plants and animals.

show abstract

Section: -Propenyl 46-o-benzylidene-2-deoxy-2-(9-fluorenylmethoxycamentioning

confidence: 65%

“…We have established the efficient synthesis of lipid A and analogues in our previous studies. 20,21,25,29 In the present study, Ru. gelatinosus lipid A 10a was synthesized using a similar strategy (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Rubrivivax gelatinosus Lipid A and Analogues for Investigation of the Structural Basis for Immunostimulating and Inhibitory Activities

Fukase¹,

Fujimoto²,

Adachi³

et al. 2008

Bulletin of the Chemical Society of Japan

Self Cite

View full text Add to dashboard Cite

show abstract

“…Chemical syntheses of pure lipid A molecular species (the endotoxin component of LPS) and of various lipid A analogs have been reported (16,(38)(39)(40)(41). The most relevant of these compounds, such as E. coli lipid A 38, are not easy to prepare and are not readily available to the scientific community.…”

Section: Discussionmentioning

confidence: 99%

“…The most relevant of these compounds, such as E. coli lipid A 38, are not easy to prepare and are not readily available to the scientific community. Kdo 2 -Lipid A represents an even greater synthetic challenge than lipid A per se (39). To date, its synthesis has been reported by only one group of investigators (39).…”

Section: Discussionmentioning

confidence: 99%

Kdo2-Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4

Raetz

Garrett

Reynolds

et al. 2006

Journal of Lipid Research

209

248

View full text Add to dashboard Cite

The LIPID MAPS Consortium (www.lipidmaps. org) is developing comprehensive procedures for identifying all lipids of the macrophage, following activation by endotoxin. The goal is to quantify temporal and spatial changes in lipids that occur with cellular metabolism and to develop bioinformatic approaches that establish dynamic lipid networks. To achieve these aims, an endotoxin of the highest possible analytical specification is crucial. We now report a large-scale preparation of 3-deoxy-D-manno-octulosonic acid (Kdo) 2 -Lipid A, a nearly homogeneous Re lipopolysaccharide (LPS) sub-structure with endotoxin activity equal to LPS. Kdo 2 -Lipid A was extracted from 2 kg cell paste of a heptose-deficient Escherichia coli mutant. It was purified by chromatography on silica, DEAE-cellulose, and C18 reverse-phase resin. Structure and purity were evaluated by electrospray ionization/mass spectrometry, liquid chromatography/mass spectrometry and 1 H-NMR. Its bioactivity was compared with LPS in RAW 264.7 cells and bone marrow macrophages from wild-type and toll-like receptor 4 (TLR-4)-deficient mice. Cytokine and eicosanoid production, in conjunction with gene expression profiling, were employed as readouts. Kdo 2 -Lipid A is comparable to LPS by these criteria. Its activity is reduced by . The LIPID MAPS consortium is developing quantitative methods for evaluating the composition, biosynthesis, and function of all macrophage lipids (1). These amphipathic substances not only are structural components of biological membranes but also play important roles in the pathophysiology of inflammation, atherosclerosis, and growth control. Additional lipid functions should emerge from the comprehensive analysis of macrophage lipids. Electrospray ionization/mass spectrometry (ESI/MS) (2, 3), coupled with prefractionation methods like reversephase liquid chromatography (LC), is being applied systematically to set the stage for the seamless integration of lipid metabolism into the broader fields of genomics, proteomics, and systems biology. To facilitate this endeavor, LIPID MAPS has introduced a new comprehensive classification system for biological lipids, amenable to computer-based data processing and substructure comparison (4). The eight LIPID MAPS categories are 1) fatty acyls, 2) glycerolipids, 3) glycerophospholipids, 4) sphingolipids, 5) sterol lipids, 6) prenol lipids, 7) saccharolipids,

show abstract

“…The isopropylidene group of the resultant tetrasaccharide derivative 13 was selectively removed under mild acidic conditions and then the allyl glycoside was cleaved. Glycosyl phosphorylation and the final hydrogenolytic deprotection gave the first synthetic Re LPS 5 (41).…”

Section: Synthesis Of Structural Analogues and Derivatives Of Lipid Amentioning

confidence: 99%

Synthesis and Functional Study of Bacterial Glycoconjugates Triggering the Innate Immune System of Higher Animals

Kusumoto

2010

TIGG

Self Cite

View full text Add to dashboard Cite

Typical bacterial glycoconjugates, lipopolysaccharide (LPS) and peptidoglycan (PGN), which ubiquitously occur in a wide range of bacterial cells as important components of their cell envelope, have long been known to enhance the immunological responses of higher animals. Synthetic works and related biological investigations on LPS are reviewed which were performed to understand the molecular basis of this phenomena mainly by the author's and collaborating groups. Structural study followed by chemical synthesis of glycolipid part of LPS, named lipid A, proved it to exhibit all the biological activity described for LPS. Synthetic homogeneous lipid A and its derivatives were utilized for precise studies of their biological functions and interaction with receptor proteins. Similar research on PGN led to conclude its minimum active structure as muramyl dipeptide. Chemical synthesis gave unequivocal evidences for the concept that definite small molecular parts of LPS and PGN are recognized by its specific receptors and trigger our defense system which is now recognized as innate immunity.

show abstract

First Total Synthesis of the Re-Type Lipopolysaccharide

Abstract: Three sequential efficient glycosylation reactions starting from D‐glucosamine were used in the first total synthesis of Escherichia coli Re lipopolysaccharide, which is one of the most simple lipopolysaccharides found on the surface of living bacteria.

Cited by 108 publications

References 48 publications

Synthesis of Rubrivivax gelatinosus Lipid A and Analogues for Investigation of the Structural Basis for Immunostimulating and Inhibitory Activities

Synthesis of Rubrivivax gelatinosus Lipid A and Analogues for Investigation of the Structural Basis for Immunostimulating and Inhibitory Activities

Kdo2-Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4

Synthesis and Functional Study of Bacterial Glycoconjugates Triggering the Innate Immune System of Higher Animals

Contact Info

Product

Resources

About