The metabolic fate of 14C-labeled peptidoglycan monomer in mice I. Identification of the monomer and the corresponding pentapeptide in urine

Tomašić, Jelka; Ladešić, Branko; Valinger, Zdenka; Hršak, Ivo

doi:10.1016/0304-4165(80)90266-4

Cited by 41 publications

(19 citation statements)

References 6 publications

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“…However, in vivo studies of PGM metabolisms revealed its short-living action in mammalian organisms. It has been shown that PGM after parenteral administration is rapidly excreted in urine within the first 6 h [10]. PGM is also rapidly degraded by hydrolytic enzymes present in human and animal sera on inactive metabolic products [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory activity of novel adjuvant formulations based on Montanide ISA oil-based adjuvants and peptidoglycan monomer

Habjanec¹,

Halassy²,

Tomašić³

2008

International Immunopharmacology

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Section: Introductionmentioning

confidence: 99%

Immunomodulatory activity of novel adjuvant formulations based on Montanide ISA oil-based adjuvants and peptidoglycan monomer

Habjanec¹,

Halassy²,

Tomašić³

2008

International Immunopharmacology

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“…The role of each Nod stimulatory molecule is still unclear. Soluble PGN fragments are known to be rapidly degraded by host N-acetylmuramyl-L-alanine amidase and eliminated into the urine (31). However, the rate of metabolic turnover of lipophilic Nod stimulatory molecules including lipids I and II by the host is unknown, and this might be important for the induction and regulation of the immune response against bacteria.…”

Section: Synthetic Lipophilic Ie-dap-containing Molecules Stimulate Nmentioning

confidence: 99%

A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses

Hasegawa

Kawasaki

Yang

et al. 2007

Journal of Biological Chemistry

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Nod1 is an intracellular protein that is involved in recognition of bacterial molecules and whose genetic variation has been linked to several inflammatory diseases. Previous studies suggested that the recognition core of Nod1 stimulatory molecules is ␥-D-glutamyl-meso-diaminopimelic acid (iE-DAP), but the identity of the major Nod1 stimulatory molecule produced by bacteria remains unknown. Here we show that bacteria produce lipophilic molecules capable of stimulating Nod1. Analysis of synthetic compounds revealed stereoselectivity of the DAP residue and that conjugation of lipophilic acyl residues specifically enhances the Nod1 stimulatory activity of the core iE-DAP. Furthermore, we demonstrate that lipophilic molecules induce and/or enhance the secretion of innate immune mediators from primary mouse mesothelial cells and human monocytic MonoMac6 cells, and this effect is mediated through Nod1. These results provide insight into the mechanism of immune recognition via Nod1, which might be useful in the design and testing of novel immunoregulators.The innate immune receptors recognize specific molecules that are commonly found in microbes and induce host defense responses to eliminate invading pathogens (1). These pathogen-recognizing receptors include membrane-bound Toll-like receptors (TLRs) 2 as well as cytosolic Nod-like receptors and RIG-I family proteins. These three classes of pathogen-recognizing receptors regulate innate and acquired immune responses by inducing intracellular signaling pathways that lead to the activation of p38, c-Jun NH 2 -terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), caspase-1, and transcription factors including NF-B and/or IRFs (1).Nod1 is the founding member of the Nod-like receptor protein family that contains nucleotide oligomerization domain (NOD) and ligand-recognizing leucine-rich repeats. This family is comprised of more than 20 members including Nod2, cryopyrin, Ipaf, NAIP, and NALP1 (1, 2). Genetic studies have revealed that variations of the NOD1 gene are associated with susceptibility to several human disorders including allergic diseases (3-5), Crohn disease (6), and sarcoidosis (7), although the mechanism underlying these disease associations remains poorly understood. Although Nod2 recognizes the muramyl dipeptide (MDP) structure in bacterial peptidoglycan (PGN)-related molecules, Nod1 senses the essential iE-DAP dipeptide, which is uniquely found in PGN of all Gram-negative and certain Gram-positive bacteria (8 -12). Previous studies suggested the involvement of Nod1 in the recognition of numerous bacteria including Helicobacter pylori (13,14), Listeria monocytogenes (15, 16), Shigella flexneri (17), several Bacillus species (18), and Propionibacterium acnes (7). Although the iE-DAP structure is found in the insoluble fraction of intact PGN, intermediates of PGN synthesis and cleaved PGN products produced during bacterial growth and PGN recycling (11,19), the identity of the major Nod1 stimulatory molecule (s) remains unknown (18). Previous s...

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“…High-MW PG-polysaccharide complexes persist, causing chronic inflammation (12). In contrast, small subunits of PG are rapidly eliminated in vivo (1,15,35,45) and cause acute but not chronic inflammation (8,24,27,46). In either situation, it is extremely difficult to detect the inflammatory agent using standard microbiological techniques.…”

mentioning

confidence: 99%

“…Persistence of bacterial debris occurs despite partial degradation by mammalian enzymes, including lysozyme (19) and muramyl-L-alanine amidase (28). Solubilized cell wall fragments have also been shown to be excreted in the urine (45).…”

mentioning

confidence: 99%

Failure To Detect Muramic Acid in Normal Rat Tissues but Detection in Cerebrospinal Fluids from Patients with Pneumococcal Meningitis

et al. 2000

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Muramic acid serves as a marker for the presence of bacterial cell wall debris in mammalian tissues. There have been a number of controversial and sometimes conflicting results on assessing the levels of muramic acid in health and disease. The present report is the first to use the state-of-the art technique, gas chromatographytandem mass spectrometry, to identify and quantify the levels of muramic acid in tissues. Muramic acid was not found in normal rat brain or spleen. However, when tissues were spiked with muramic acid, it was readily identified. The detection limit was <1 ng of muramic acid/100 mg (wet weight) of tissue. The levels of muramic acid reported in diseased human spleen and spleen of arthritic rats, previously injected with bacterial cell walls, were 100-to 1,000-fold higher. In the present study, muramic acid was also readily detected in the cerebrospinal fluid of patients with pneumococcal meningitis (6.8 to 3,900 ng of muramic acid/ml of cerebrospinal fluid). In summary, there can be an enormous difference in the levels of muramic acid found in different mammalian tissues and body fluids in health and disease. This report could have great impact in future studies assessing the role of bacterial cell wall remnants in the pathogenesis of certain human inflammatory diseases.

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The metabolic fate of 14C-labeled peptidoglycan monomer in mice I. Identification of the monomer and the corresponding pentapeptide in urine

Cited by 41 publications

References 6 publications

Immunomodulatory activity of novel adjuvant formulations based on Montanide ISA oil-based adjuvants and peptidoglycan monomer

Immunomodulatory activity of novel adjuvant formulations based on Montanide ISA oil-based adjuvants and peptidoglycan monomer

A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses

Failure To Detect Muramic Acid in Normal Rat Tissues but Detection in Cerebrospinal Fluids from Patients with Pneumococcal Meningitis

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