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Proc. Jpn. Acad., Ser. B 86 (2010)

[Vol. 86,

Review Key structures of bacterial peptidoglycan and lipopolysaccharide triggering the innate immune system of higher animals: Chemical synthesis and functional studies
By Shoichi KUSUMOTO,Ã1,† Koichi FUKASEÃ2 and Tetsuo SHIBAÃ3
" (Communicated by Satoshi OMURA, M.J.A.)

Abstract: Chemistry-based investigation is reviewed which led toidentication of the active entities responsible for the immunostimulating potencies of peptidoglycan and lipopolysaccharide. Though these glycoconjugates which ubiquitously occur in wide range of bacteria as the essential components of their cell envelopes have long been known to enhance the immunological responses of higher animals, neither the precise chemical structures required nor themechanism of their action remained to be elucidated until early 1970s. Chemical synthesis of partial structures of peptidoglycan proved N-acetylmuramyl-L-alanyl-D-isoglutamine to be the minimum structure responsible for the activity and led to later identication of its receptor protein Nod2 present in animal cells. Another active partial structure of peptidoglycan, g-D-glutamylmeso-diaminopimelic acid,and its receptor Nod1 were also identied as well. With regard to lipopolysaccharide, its glycolipid part named lipid A was puried and the structure studied. Chemically synthesized lipid A according to the newly elucidated structure exhibited full activity described for lipopolysaccharide known as endotoxin. Synthetic homogeneous lipid A and its structural analogues and labeled derivativesenabled precise studies of their interaction with receptor proteins and the mechanism of their action. Chemical synthesis of homogeneous partial structures of peptidoglycan and lipopolysaccharide gave unequivocal evidences for the concept that denite small molecular parts of these complex macromolecular bacterial glycoconjugates are specically recognized by their respective receptors and trigger ourdefense system now widely recognized as innate immunity. Keywords: innate immunity chemical synthesis, muramyl peptides, lipid A, peptidoglycan, lipopolysaccharide,

Introduction Bacterial cells and some of their typical components have long been known to enhance the immunological response of higher animals. When simultaneously applied with antigenic proteins to experimental animals, heat-killedMycobacterium cells, for example, strongly enhances the production of
Ã1 Ã2

Suntory Institute for Bioorganic Research, Osaka, Japan. Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan. Ã3 Protein Research Foundation, Osaka, Japan. † Correspondence should be addressed: S. Kusumoto, Suntory Institute for Bioorganic Research, Wakayamadai 1-1-1, Shimamotocho,Mishima-gun, Osaka 618-8503, Japan (e-mail: skus@sunbor. or.jp).

specic antibodies against the relevant antigens.1) Endotoxin of Gram-negative bacteria was also known as one of the most potent immunostimulants.2) Intensive studies have been carried out by microbiologists, biochemists, and immunologists to understand the details of these highly interesting phenomena and their molecular mechanism.Until early 1970s, two typical bacterial glycoconjugates, i.e., peptidoglycan (PGN) and lipopolysaccharide (LPS), the latter being the active entity of endotoxin, were shown to be major active cell components responsible for the immunostimulative function attributed to bacterial cells.2),3) PGN is a vital cell wall component shared by all types of bacteria, while LPS is an essential structuralelement of the outer membrane present in all Gram-negative bacterial cells. No information was,

doi: 10.2183/pjab.86.322 62010 The Japan Academy

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Key bacterial surface molecules triggering innate immune system

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however, available of their active structures because of the complex and heterogeneous structures of these bacterial high molecular weight glycoconjugates. In view of...