Faculty Opinions recommendation of An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid.

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso-diaminopimelic acid (mesoDAP) and activates the innate immune system. Interestingly, a few pathogenic and commensal bacteria modify their PG stem peptide by amidation of mesoDAP (mesoDAPNH2). In the present study, NOD1 stimulation assays were performed using bacterial PG containing mesoDAP (PGDAP) and mesoDAPNH2 (PGDAPNH2) to understand the differences in their biomolecular recognition mechanism. PGDAP was effectively recognized, whereas PGDAPNH2 showed reduced recognition by the NOD1 receptor. Restimulation of the NOD1 receptor, which was initially stimulated with PGDAP using PGDAPNH2, did not show any further NOD1 activation levels than with PGDAP alone. But the NOD1 receptor initially stimulated with PGDAPNH2 responded effectively to restimulation with PGDAP. The biomolecular structure–recognition relationship of the ligand-sensing leucine-rich repeat (LRR) domain of human NOD1 (NOD1–LRR) with PGDAP and PGDAPNH2 was studied by different computational techniques to further understand the molecular basis of our experimental observations. The d-Glu–mesoDAP motif of GMTPDAP, which is the minimum essential motif for NOD1 activation, was found involved in specific interactions at the recognition site, but the interactions of the corresponding d-Glu–mesoDAP motif of PGDAPNH2 occur away from the recognition site of the NOD1 receptor. Hot-spot residues identified for effective PG recognition by NOD1–LRR include W820, G821, D826 and N850, which are evolutionarily conserved across different host species. These integrated results thus successfully provided the atomic level and biochemical insights on how PGs containing mesoDAPNH2 evade NOD1–LRR receptor recognition.

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The Frameshift Mutation in Nod2 Results in Unresponsiveness Not Only to Nod2- but Also Nod1-activating Peptidoglycan Agonists

Journal of Biological Chemistry ◽

10.1074/jbc.m504924200 ◽

2005 ◽

Vol 280 (43) ◽

pp. 35859-35867 ◽

Cited By ~ 64

Author(s):

Mihai G. Netea ◽

Gerben Ferwerda ◽

Dirk J. de Jong ◽

Catherine Werts ◽

Ivo G. Boneca ◽

...

Keyword(s):

Crohn Disease ◽

Frameshift Mutation ◽

Susceptibility Gene ◽

Muramyl Dipeptide ◽

Protein S ◽

Diaminopimelic Acid ◽

Gram Negative ◽

Peptidoglycan Recognition Protein ◽

Recognition Protein ◽

Bacterial Peptidoglycan

NOD2/CARD15 is the first characterized susceptibility gene in Crohn disease. The Nod2 1007fs (Nod2fs) frameshift mutation is the most prevalent in Crohn disease patients. Muramyl dipeptide from bacterial peptidoglycan is the minimal motif detected by Nod2 but not by Nod2fs. Here we investigated the response of human peripheral blood mononuclear cells (PBMCs) from Crohn disease patients not only to muramyl dipeptide but also to several other muramyl peptides. Most unexpectedly, we observed that patients homozygous for the Nod2fs mutation were totally unresponsive to MurNAc-l-Ala-d-Glu-meso-diaminopimelic acid (DAP) (M-TriDAP), the specific agonist of Nod1, and to Gram-negative bacterial peptidoglycan. In contrast, PBMCs from a patient homozygous for the Nod2 R702W mutation, also associated with Crohn disease, displayed normal response to Gram-negative bacterial peptidoglycan. In addition, the blockage of the Nod1/M-TriDAP pathway could be partially overcome by co-stimulation with the Toll-like receptors agonists lipoteichoic acid or lipopolysaccharide. Investigation into the mechanism of this finding revealed that Nod2fs did not act as a dominant-negative molecule for the Nod1/M-TriDAP pathway, implying that the blockage is dependent upon the expression or activity of other factors. We demonstrated that PBMCs from Nod2fs patients express high levels of the peptidoglycan recognition protein S, a secreted protein known to interact with muramyl peptides. We proposed that through a scavenger function, peptidoglycan recognition protein S may dampen M-TriDAP-dependent responses in Nod2fs patients. Together, our results identified a cross-talk between the Nod1 and Nod2 pathways and suggested that down-regulation of Nod1/M-TriDAP pathway may be associated with Crohn disease.

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Zum Wirkungsmechanismus von Penicillin

Zeitschrift für Naturforschung B ◽

10.1515/znb-1965-0213 ◽

1965 ◽

Vol 20 (2) ◽

pp. 153-157 ◽

Cited By ~ 14

Author(s):

U. Schwarz ◽

W. Weidel

Keyword(s):

Essential Role ◽

Diaminopimelic Acid ◽

Balanced Growth ◽

E Coli ◽

Radioactive Labelling

By radioactive labelling with 14C-diaminopimelic acid it was possible to show, that diaminopimelic acid-containing oligopeptides, isolated from penicillin-induced spheroplasts of E. coli B. were liberated from murein as well as from murein precursors under the effect of the antibiotic. This indicates that the inhibition of murein synthesis, caused by penicillin, results in a degradation of the sacculus by mureinases which normally play an essential role in the balanced growth of the sacculus 1.

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Peptidoglycan hydrolase of an unusual cross-link cleavage specificity contributes to bacterial cell wall synthesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816893116 ◽

2019 ◽

Vol 116 (16) ◽

pp. 7825-7830 ◽

Cited By ~ 8

Author(s):

Pavan Kumar Chodisetti ◽

Manjula Reddy

Keyword(s):

Cytoplasmic Membrane ◽

Hydrolytic Enzyme ◽

Diaminopimelic Acid ◽

Peptidoglycan Hydrolase ◽

Cross Link ◽

E Coli ◽

Cleavage Specificity ◽

Peptidoglycan Synthesis ◽

Cross Links ◽

Bacterial Peptidoglycan

Bacteria are surrounded by a protective exoskeleton, peptidoglycan (PG), a cross-linked mesh-like macromolecule consisting of glycan strands interlinked by short peptides. Because PG completely encases the cytoplasmic membrane, cleavage of peptide cross-links is a prerequisite to make space for incorporation of nascent glycan strands for its successful expansion during cell growth. In most bacteria, the peptides consist ofl-alanine,d-glutamate,meso-diaminopimelic acid (mDAP) andd-alanine (d-Ala) with cross-links occurring either betweend-Ala and mDAP or two mDAP residues. InEscherichia coli, thed-Ala−mDAP cross-links whose cleavage by specialized endopeptidases is crucial for expansion of PG predominate. However, a small proportion of mDAP−mDAP cross-links also exist, yet their role in the context of PG expansion or the hydrolase(s) capable of catalyzing their cleavage is not known. Here, we identified an ORF of unknown function, YcbK (renamed MepK), as an mDAP−mDAP cross-link cleaving endopeptidase working in conjunction with other elongation-specific endopeptidases to make space for efficient incorporation of nascent PG strands into the sacculus.E. colimutants lackingmepKand anotherd-Ala−mDAP–specific endopeptidase (mepS) were synthetic sick, and the defects were abrogated by lack ofl,d-transpeptidases, enzymes catalyzing the formation of mDAP cross-links. Purified MepK was able to cleave the mDAP cross-links of soluble muropeptides and of intact PG sacculi. Overall, this study describes a PG hydrolytic enzyme with a hitherto unknown substrate specificity that contributes to expansion of the PG sacculus, emphasizing the fundamental importance of cross-link cleavage in bacterial peptidoglycan synthesis.

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Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity

Blood ◽

10.1182/blood-2005-02-0530 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2551-2558 ◽

Cited By ~ 94

Author(s):

Ju Hyun Cho ◽

Iain P. Fraser ◽

Koichi Fukase ◽

Shoichi Kusumoto ◽

Yukari Fujimoto ◽

...

Keyword(s):

Innate Immunity ◽

Antimicrobial Effect ◽

Protein S ◽

Host Recognition ◽

Human Neutrophils ◽

Peptidoglycan Recognition Protein ◽

Acid Type ◽

Potential Synergy ◽

Recognition Protein ◽

Bacterial Peptidoglycan

AbstractInnate immune responses to bacteria require cooperative interactions between host recognition molecules and phagocytes. The peptidoglycan recognition proteins (PGRPs) are a large group of proteins found in insects and mammals that bind to bacterial peptidoglycan (PGN). PGRP-S is located with other antimicrobial proteins, such as lysozyme, in the granules of human neutrophils. Whereas both PGRP-S and lysozyme recognize PGN, the exact binding specificity of human PGRP-S, its functional activity, and its potential synergy with other neutrophil-derived bactericidal proteins such as lysozyme have not been determined. Here we show that human PGRP-S binds to and inhibits the growth of Staphylococcus aureus (containing lysine-type PGN) and Escherichia coli (containing mesodiaminopimelic acid-type PGN). The binding affinity and thus antimicrobial activity of PGRP-S is determined by the third amino acid in the PGN stem peptide. Furthermore, the antimicrobial effect of PGRP-S against E coli is synergistic with lysozyme, and lysozyme and PGRP-S colocalize in neutrophil extracellular traps (NETs), suggesting that these granule-derived proteins act together to kill bacteria trapped in the NETs. Taken together, these results indicate that human PGRP-S plays a role in innate immunity in the context of neutrophils by contributing to the killing of intracellular and extracellular bacteria. (Blood. 2005;106:2551-2558)

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An Arabidopsis homolog of the bacterial peptidoglycan synthesis enzyme MurE has an essential role in chloroplast development

The Plant Journal ◽

10.1111/j.1365-313x.2007.03379.x ◽

2007 ◽

Vol 53 (6) ◽

pp. 924-934 ◽

Cited By ~ 49

Author(s):

Marlon Garcia ◽

Fumiyoshi Myouga ◽

Katsuaki Takechi ◽

Hiroshi Sato ◽

Kazuma Nabeshima ◽

...

Keyword(s):

Essential Role ◽

Chloroplast Development ◽

Peptidoglycan Synthesis ◽

Bacterial Peptidoglycan ◽

Arabidopsis Homolog

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Faint Hα Emission in the Corona and Its Relation to the Prominences

International Astronomical Union Colloquium ◽

10.1017/s0252921100025550 ◽

1994 ◽

Vol 144 ◽

pp. 339-342

Author(s):

V. N. Dermendjiev ◽

Z. Mouradian ◽

J.- L. Leroy ◽

P. Duchlev

Keyword(s):

Magnetic Field ◽

Solar Corona ◽

Essential Role ◽

Hα Emission

AbstractThe relation between episodically observed in the solar corona faint Hαemission structures and the long lived prominences was studied. Particular consideration was given for cases in which the corresponding prominences had undergone DB process. An MHD interpretation of the phenomenon “emissions froides” (cool emission) is proposed in which an essential role plays the prominence supporting magnetic field.

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