Author: "Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)" / Topic: 030304 developmental biology - Searchworks@Jio Institute Digital Library Search Results

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Start Over Author "Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)" Topic 030304 developmental biology

18 results on '"Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

1. Association of the Pro12Ala and C1431T Variants ofPPARγ and Their Haplotypes with Susceptibility to Gestational Diabetes

Author: Barbara Heude, Jean-François Bedel, Jean-Marc Lacorte, Anne Forhan, Véronique Pelloux, Marie-Aline Charles, Karine Clément, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), G. Liccardi, I. Annesi-Maesano 1, A. Salzillo, G. D'amato Liccardi G, Annesi-Maesano I, Salzillo A, D'Amato G. Collaboration, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : DNA, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, MESH : Genotype, Type 2 diabetes, Biochemistry, Body Mass Index, MESH: Genotype, Cohort Studies, MESH: Pregnancy, 0302 clinical medicine, Endocrinology, Gene Frequency, Pregnancy, Odds Ratio, Medicine, MESH : Female, MESH : Gene Frequency, MESH: Genetic Variation, MESH: Cohort Studies, MESH: Genetic Association Studies, MESH: Diabetes, Gestational, 2. Zero hunger, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: DNA, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Adult, 3. Good health, Gestational diabetes, Female, MESH : PPAR gamma, Adult, medicine.medical_specialty, Genotype, MESH : Cohort Studies, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, MESH: Body Mass Index, 03 medical and health sciences, MESH : Genetic Variation, Diabetes mellitus, Internal medicine, MESH: Gene Frequency, Humans, MESH : Haplotypes, Genetic Association Studies, 030304 developmental biology, MESH: Humans, business.industry, MESH : Humans, Biochemistry (medical), Haplotype, Genetic Variation, MESH: Adult, MESH : Genetic Association Studies, MESH: Haplotypes, DNA, Odds ratio, medicine.disease, Obesity, MESH: Odds Ratio, PPAR gamma, MESH : Body Mass Index, MESH : Pregnancy, Diabetes, Gestational, MESH: PPAR gamma, Haplotypes, MESH : Odds Ratio, MESH : Diabetes, Gestational, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, Body mass index
Abstract: International audience; BACKGROUND: The protective role of the Ala allele in the Pro12Ala polymorphism of PPARγ on type 2 diabetes has been well established but not confirmed in the context of pregnancy, for gestational diabetes, a known predictor of later type 2 diabetes onset. Another PPARγ polymorphism, the C1431T, is in strong linkage disequilibrium with Pro12Ala and has been shown to be associated with body weight, but its association with diabetes is controversial. RESEARCH DESIGN AND METHODS: In 1708 women of the EDEN mother-child cohort, the PPARγ Pro12Ala and C1431T polymorphisms were genotyped and analyzed in association with maternal prepregnancy body mass index, obesity before pregnancy, and gestational diabetes, separately and also combined in haplotypes. RESULTS: The prevalence of obesity was significantly higher in mothers with the Ala/Ala genotype compared with carriers of the Pro allele (35 vs. 9%, P < 0.0001), but there was no cases of gestational diabetes in Ala/Ala mothers. Mothers homozygous for the T allele of C1431T were also more obese (24 vs. 9%, P = 0.035), and three times more had gestational diabetes (18 vs. 6%, P = 0.044). Frequencies of haplotypes for these two single-nucleotide polymorphisms differed significantly in mothers with and without gestational diabetes; in comparison with the Pro-C haplotype, the Pro-T haplotype conferred the highest risk [odds ratio (95% CI) = 1.89 (1.05-3.40)], and the Ala-C the lowest risk [odds ratio (95% CI) = 0.12 (0.52-1.70)]. CONCLUSIONS: These results from a haplotype analysis, show for the first time that genetic variations in the PPARγ gene could play a role in the susceptibility to develop gestational diabetes.
Published: 2011

2. Serine/threonine protein phosphatase-mediated control of the peptidoglycan cross-linking L,D-transpeptidase pathway in Enterococcus faecium

Author: Jean-Luc Mainardi, Nathalie Josseaume, Emmanuelle Sacco, Michel Arthur, Mélanie Cortes, Louis B. Rice, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brown University, Service de Microbiologie [CHU GeorgesPompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and HAL UPMC, Gestionnaire
Subjects: Phosphatase, Enterococcus faecium, Peptidoglycan, Biology, [ SDV.MP.BAC ] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Pentapeptide repeat, Microbiology, Dephosphorylation, Serine, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Virology, Phosphoprotein Phosphatases, Protein phosphorylation, Protein kinase A, 030304 developmental biology, 0303 health sciences, Peptidoglycan glycosyltransferase, 030306 microbiology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QR1-502, chemistry, Biochemistry, Peptidoglycan Glycosyltransferase, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Research Article
Abstract: The last step of peptidoglycan polymerization involves two families of unrelated transpeptidases that are the essential targets of β-lactam antibiotics. d,d-transpeptidases of the penicillin-binding protein (PBP) family are active-site serine enzymes that use pentapeptide precursors and are the main or exclusive cross-linking enzymes in nearly all bacteria. However, peptidoglycan cross-linking is performed mainly by active-site cysteine l,d-transpeptidases that use tetrapeptides in Mycobacterium tuberculosis, Clostridium difficile, and β-lactam-resistant mutants of Enterococcus faecium. We have investigated reprogramming of the E. faecium peptidoglycan assembly pathway by a switch from pentapeptide to tetrapeptide precursors and bypass of PBPs by l,d-transpeptidase Ldtfm. Mutational alterations of two signal transduction systems were necessary and sufficient for activation of the l,d-transpeptidation pathway, which is essentially cryptic in wild-type strains. The first one is a classical two-component regulatory system, DdcRS, that controls the activity of Ldtfm at the substrate level. As previously described, loss of DdcS phosphatase activity leads to production of the d,d-carboxypeptidase DdcY and conversion of the pentapeptide into the tetrapeptide substrate of Ldtfm. Here we show that full bypass of PBPs by Ldtfm also requires increased Ser/Thr protein phosphorylation resulting from impaired activity of phosphoprotein phosphatase StpA. This enzyme negatively controlled the level of protein phosphorylation both by direct dephosphorylation of target proteins and by dephosphorylation of its cognate kinase Stk. In combination with production of DdcY, increased protein phosphorylation by this eukaryotic-enzyme-like Ser/Thr protein kinase was sufficient for activation of the l,d-transpeptidation pathway in the absence of mutational alteration of peptidoglycan synthesis enzymes., IMPORTANCE The mechanism of acquisition of high-level ampicillin resistance involving bypass of the penicillin-binding proteins (PBPs) by l,d-transpeptidase Ldtfm was incompletely understood, as production of tetrapeptide precursors following transcriptional activation of the ddc locus by the DdcRS two-component regulatory system was necessary but not sufficient for full activation of the l,d-transpeptidation pathway. Here, we identified the release of a negative control of Ser/Thr protein phosphorylation mediated by phosphatase StpA as the additional factor essential for ampicillin resistance. Thus, bypass of PBPs by Ldtfm requires the modification of signal transduction regulatory systems without any gain of function by mutational alteration of peptidoglycan biosynthetic enzymes. In contrast, previously characterized mechanisms of antibiotic resistance involve horizontal gene transfer and mutational alteration of drug targets. Activation of the l,d-transpeptidation pathway reported in this study is an unprecedented mechanism of emergence of a new metabolic pathway since it involved the recruitment of preexisting functions following modifications of regulatory circuits.
Published: 2014

3. Specificity determinants for the two tRNA substrates of the cyclodipeptide synthase AlbC from Streptomyces noursei

Author: Matthieu Fonvielle, Mireille Moutiez, Emmanuel Favry, Isabelle Jacques, Michel Arthur, Muriel Gondry, Pascal Belin, Jérôme Seguin, Service d’Ingénierie Moléculaire des Protéines, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UPMC, Gestionnaire, Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: RNA, Transfer, Leu, RNA, Transfer, Amino Acyl, 01 natural sciences, Streptomyces, Substrate Specificity, [PHYS] Physics [physics], 03 medical and health sciences, RNA, Transfer, Phe, Bacterial Proteins, Genetics, Binding site, Peptide Synthases, 030304 developmental biology, [PHYS]Physics [physics], 0303 health sciences, [ PHYS ] Physics [physics], Binding Sites, biology, ATP synthase, 010405 organic chemistry, Nucleic Acid Enzymes, Substrate (chemistry), biology.organism_classification, 0104 chemical sciences, Streptomyces noursei, Biochemistry, Transfer RNA, Helix, biology.protein, Leucine
Abstract: International audience; Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNA substrates in a sequential ping-pong mechanism to form a cyclodipeptide. The crystal structures of three CDPSs have been determined and all show a Rossmann-fold domain similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs). Structural features and mutational analyses however suggest that CDPSs and aaRSs interact differently with their tRNA substrates. We used AlbC from Streptomyces noursei that mainly produces cyclo(l-Phe-l-Leu) to investigate the interaction of a CDPS with its substrates. We demonstrate that Phe-tRNA Phe is the first substrate accommodated by AlbC. Its binding to AlbC is dependent on basic residues located in the helix ␣4 that form a basic patch at the surface of the protein. AlbC does not use all of the Leu-tRNA Leu isoacceptors as a second substrate. We show that the G 1-C 72 pair of the acceptor stem is essential for the recognition of the second substrate. Substitution of D163 located in the loop ␣6–␣7 or D205 located in the loop ␤6–␣8 affected Leu-tRNA Leu isoacceptors specificity, suggesting the involvement of these residues in the binding of the second substrate. This is the first demonstration that the two substrates of CDPSs are accommodated in different binding sites.
Published: 2014

4. Colicin M, a peptidoglycan lipid-II-degrading enzyme: potential use for antibacterial means?

Author: Delphine Patin, Dominique Mengin-Lecreulx, Thierry Touzé, Aurélie Barnéoud-Arnoulet, Roland Lloubès, Ahmed Bouhss, Didier Blanot, Michel Arthur, Hélène Barreteau, Denis Duché, Emmanuelle Sacco, Meriem El Ghachi, Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Enveloppes Bactériennes et Antibiotiques, Département Microbiologie (Dpt Microbio), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Département Microbiologie ( Dpt Microbio ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut de biochimie et biophysique moléculaire et cellulaire ( IBBMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire d'ingénierie des systèmes macromoléculaires ( LISM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Enveloppes Bactériennes et Antibiotiques ( ENVBAC )
Subjects: Models, Molecular, Isomerase activity, Protein Conformation, Colicins, Peptidoglycan, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Protein structure, Bacteriocin, Bacteriocins, Antibiosis, medicine, Escherichia coli, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, Lipid II, 030306 microbiology, Periplasmic space, Uridine Diphosphate N-Acetylmuramic Acid, Anti-Bacterial Agents, chemistry, Colicin
Abstract: International audience; Colicins are proteins produced by some strains of Escherichia coli to kill competitors belonging to the same species. Among them, ColM (colicin M) is the only one that blocks the biosynthesis of peptidoglycan, a specific bacterial cell-wall polymer essential for cell integrity. ColM acts in the periplasm by hydrolysing the phosphoester bond of the peptidoglycan lipid intermediate (lipid II). ColM cytotoxicity is dependent on FkpA of the targeted cell, a chaperone with peptidylprolyl cis-trans isomerase activity. Dissection of ColM was used to delineate the catalytic domain and to identify the active-site residues. The in vitro activity of the isolated catalytic domain towards lipid II was 50-fold higher than that of the full-length bacteriocin. Moreover, this domain was bactericidal in the absence of FkpA under conditions that bypass the import mechanism (FhuA-TonB machinery). Thus ColM undergoes a maturation process driven by FkpA that is not required for the activity of the isolated catalytic domain. Genes encoding proteins with similarity to the catalytic domain of ColM were identified in pathogenic strains of Pseudomonas and other genera. ColM acts on several structures of lipid II representative of the diversity of peptidoglycan chemotypes. All together, these data open the way to the potential use of ColM-related bacteriocins as broad spectrum antibacterial agents.
Published: 2012

5. Characterization of colicin M and its orthologs targeting bacterial cell wall peptidoglycan biosynthesis

Author: Delphine Patin, Meriem El Ghachi, Ahmed Bouhss, Michel Arthur, Mark A. Brooks, Thierry Touzé, Dominique Mengin-Lecreulx, Hélène Barreteau, Denis Duché, Emmanuelle Sacco, Fabien Gérard, Roland Lloubès, Aurélie Barnéoud-Arnoulet, Herman van Tilbeurgh, Didier Blanot, Enveloppes Bactériennes et Antibiotiques, Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'ingénierie des systèmes macromoléculaires ( LISM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de biochimie et biophysique moléculaire et cellulaire ( IBBMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), and Enveloppes Bactériennes et Antibiotiques ( ENVBAC )
Subjects: Microbiology (medical), Models, Molecular, Lysis, Immunology, Colicins, Peptidoglycan, Biology, medicine.disease_cause, Microbiology, Bacterial cell structure, Substrate Specificity, Cell wall, 03 medical and health sciences, chemistry.chemical_compound, Bacteriocin, Bacteriocins, Cell Wall, Pseudomonas, medicine, Escherichia coli, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, 030306 microbiology, Uridine Diphosphate N-Acetylmuramic Acid, Protein Structure, Tertiary, Enzyme, chemistry, Biochemistry, Colicin
Abstract: International audience; For a long time, colicin M was known for killing susceptible Escherichia coli cells by interfering with cell wall peptidoglycan biosynthesis, but its precise mode of action was only recently elucidated: this bacterial toxin was demonstrated to be an enzyme that catalyzes the specific degradation of peptidoglycan lipid intermediate II, thereby provoking the arrest of peptidoglycan synthesis and cell lysis. The discovery of this activity renewed the interest in this colicin and opened the way for biochemical and structural analyses of this new class of enzyme (phosphoesterase). The identification of a few orthologs produced by pathogenic strains of Pseudomonas further enlarged the field of investigation. The present article aims at reviewing recently acquired knowledge on the biology of this small family of bacteriocins.
Published: 2012

6. Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance

Author: Isabelle Broutin, Frédérique Maurice, Frédéric Dardel, Isabelle Podglajen, Ekkehard Collatz, Philippe Benas, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Models, Molecular, Scientific Report, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, Antibiotic resistance, Transition state analog, Acetyltransferases, Ciprofloxacin, Genetics, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, Amikacin, 030304 developmental biology, 0303 health sciences, Molecular Structure, 030306 microbiology, Mechanism (biology), Aminoglycoside, Pathogenic bacteria, Drug Resistance, Multiple, 3. Good health, Acetyltransferase, Mobile genetic elements, Gentamicins, Crystallization
Abstract: The emergence of multi-resistant pathogenic bacteria is a worldwide health issue. Recently, clinical variants of a single antibiotic-modifying acetyltransferase, AAC(6')-Ib-a variant of aminoglycoside 6'-N-acetyltransferase-have been identified that confer extended resistance to most aminoglycosides and, more surprisingly, to structurally unrelated fluoroquinolones. The corresponding gene is carried by mobile genetic elements and is present in most multi-resistant pathogenic strains, hence making it a serious threat to current therapies. Here, we report the crystal structures of both narrow- and broad-spectrum resistance variants of this enzyme, which reveal the structural basis for the emergence of extended resistance. The active site shows an important plasticity and has adapted to new substrates by a large-scale gaping process. We have also obtained co-crystals with both substrates, and with a simple transition state analogue, which provides new clues for the design of inhibitors of this resistance mechanism.
Published: 2007

7. Identification of the L,D-transpeptidases responsible for attachment of the Braun lipoprotein to Escherichia coli peptidoglycan

Author: Martine Fourgeaud, Dominique Mengin-Lecreulx, Sébastien Petit-Frère, Laurent Gutmann, Michel Arthur, Samuel Bellais, Jean-Luc Mainardi, Arul Marie, Lionel Dubost, Sophie Magnet, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), This work was supported by the European Community (COBRA, contract LSHM-CT-2003- 503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., Lecerf, Maxime, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique ( CNRS ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Enveloppes Bactériennes et Antibiotiques ( ENVBAC ), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), and Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH : Escherichia coli, MESH : Molecular Sequence Data, MESH: Peptidyl Transferases, Genomics and Proteomics, Mutant, MESH: Escherichia coli Proteins, MESH: Amino Acid Sequence, medicine.disease_cause, chemistry.chemical_compound, MESH : Peptidoglycan, 0303 health sciences, biology, MESH : Peptides, MESH: Escherichia coli, MESH: Peptides, MESH: Peptidoglycan, MESH : Amino Acid Sequence, MESH : Escherichia coli Proteins, Escherichia coli Proteins, MESH: Lipoproteins, Enterobacteriaceae, Biochemistry, Lipoproteins, Molecular Sequence Data, MESH : Lipoproteins, Peptidoglycan, Microbiology, 03 medical and health sciences, MESH : Peptidyl Transferases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Bacteriology, Escherichia coli, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Molecular Sequence Data, 030306 microbiology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, chemistry, Peptidyl Transferases, bacteria, Peptides, Bacteria, Enterococcus faecium, Lipoprotein
Abstract: The l , d -transpeptidase Ldt fm catalyzes peptidoglycan cross-linking in β-lactam-resistant mutant strains of Enterococcus faecium . Here, we show that in Escherichia coli Ldt fm homologues are responsible for the attachment of the Braun lipoprotein to murein, indicating that evolutionarily related domains have been tailored to use muropeptides or proteins as acyl acceptors in the l , d -transpeptidation reaction.
Published: 2007

8. Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes

Author: Jean-Emmanuel Hugonnet, Jean-Luc Mainardi, Martine Fourgeaud, Arul Marie, Vanessa Delfosse, Louis B. Rice, Ana Arbeloa, Michel Arthur, Sophie Magnet, Lionel Dubost, Claudine Mayer, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique ( CNRS ), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, ACI Microbiologie 2003' from the Fonds National de la Science (Grant ACIM-4-9), the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, and Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Peptidyl Transferases, Penicillin binding proteins, MESH: Sequence Homology, Amino Acid, Bacillus subtilis, MESH : Drug Resistance, Bacterial, Diaminopimelic Acid, Biochemistry, Pentapeptide repeat, Substrate Specificity, chemistry.chemical_compound, Cell Wall, Enterococcus faecalis, MESH : Bacterial Proteins, MESH : Diaminopimelic Acid, MESH : Enterococcus faecalis, MESH: Bacterial Proteins, MESH : Peptidoglycan, chemistry.chemical_classification, MESH: Penicillin-Binding Proteins, 0303 health sciences, biology, MESH : Substrate Specificity, MESH: Peptidoglycan, MESH : Bacillus subtilis, Glycopeptide, MESH : Sequence Homology, Amino Acid, Amino acid, Cysteine Endopeptidases, MESH: Oligopeptides, MESH : Cysteine Endopeptidases, Oligopeptides, MESH : Oligopeptides, MESH: Enterococcus faecalis, Stereochemistry, Gram-positive bacteria, Peptidoglycan, MESH : Penicillin-Binding Proteins, 03 medical and health sciences, MESH: Cell Wall, Bacterial Proteins, Species Specificity, MESH : Peptidyl Transferases, MESH: Drug Resistance, Bacterial, Drug Resistance, Bacterial, MESH: Species Specificity, MESH: Diaminopimelic Acid, MESH : Species Specificity, Penicillin-Binding Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH : Cell Wall, Tetrapeptide, Sequence Homology, Amino Acid, 030306 microbiology, Cell Biology, MESH: Bacillus subtilis, biology.organism_classification, chemistry, Peptidyl Transferases, MESH: Substrate Specificity, MESH: Cysteine Endopeptidases
Abstract: International audience; We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.
Published: 2007

9. The Enterococcus hirae Mur-2 enzyme displays N-acetylglucosaminidase activity

Author: Stéphane Mesnage, Sophie Magnet, Catherine Eckert, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Lecerf, Maxime, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )
Subjects: MESH : Molecular Sequence Data, MESH: Acetylglucosaminidase, MESH: Catalytic Domain, MESH: Amino Acid Sequence, Tandem mass spectrometry, Biochemistry, Mass Spectrometry, Substrate Specificity, chemistry.chemical_compound, Structural Biology, Enterococcus hirae, Catalytic Domain, chemistry.chemical_classification, 0303 health sciences, MESH : Substrate Specificity, biology, MESH : Amino Acid Sequence, MESH : Catalytic Domain, N-acetylglucosaminidase, MESH: Enterococcus, CAZy, Molecular Sequence Data, Biophysics, Article, 03 medical and health sciences, MESH : Mass Spectrometry, MESH : Acetylglucosaminidase, Acetylglucosaminidase, Hydrolase, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Glycosyl, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Molecular Sequence Data, 030306 microbiology, Autolysin, MESH : Enterococcus, Cell Biology, biology.organism_classification, Enzyme, chemistry, Enterococcus, MESH: Substrate Specificity
Abstract: International audience; Enterococcus hirae produces two autolytic enzymes named Mur-1 and Mur-2, both previously described as N-acetylmuramidases. We used tandem mass spectrometry to show that Mur-2 in fact displays N-acetylglucosaminidase activity. This result reveals that Mur-2 and its counterparts studied to date, which are members of glycosyl hydrolase family 73 from the CAZy (Carbohydrate-Active enZyme) database, display the same catalytic activity.
Published: 2007

10. Novel mechanism of resistance to glycopeptide antibiotics in Enterococcus faecium

Author: Arul Marie, J.-C. Quincampoix, Jean-Emmanuel Hugonnet, Louis B. Rice, Laurent Gutmann, Julie Cremniter, Nathalie Josseaume, Lionel Dubost, Jean-Luc Mainardi, Michel Arthur, Lecerf, Maxime, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, This work was supported by the European Community (COBRA, contract LSHM-CT-2003-503335, 6th PCRD), the National Institute of Allergy and Infectious Diseases (Grant R01 AI45626), and the Fondation pour la Recherche Médicale., Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Chimie et Biochimie des Substances Naturelles, and Centre National de la Recherche Scientifique ( CNRS )
Subjects: Cytoplasm, MESH : Muramoylpentapeptide Carboxypeptidase, Enterococcus faecium, MESH : Models, Biological, Muramoylpentapeptide Carboxypeptidase, MESH : Drug Resistance, Bacterial, Biochemistry, Substrate Specificity, Muramoylpentapeptide carboxypeptidase, chemistry.chemical_compound, polycyclic compounds, Peptide bond, MESH: Enterococcus faecium, MESH : Anti-Bacterial Agents, MESH : Enterococcus faecium, MESH: Peptide Fragments, MESH : Peptidoglycan, Alanine, 0303 health sciences, MESH: Microbial Sensitivity Tests, MESH : Substrate Specificity, MESH: Peptidoglycan, Hydrolysis, Glycopeptides, MESH: Amino Acid Substitution, Glycopeptide, Anti-Bacterial Agents, Cross-Linking Reagents, MESH: Muramoylpentapeptide Carboxypeptidase, MESH: Hydrolysis, MESH : Cross-Linking Reagents, MESH : Cytoplasm, MESH : Glycopeptides, Stereochemistry, MESH: Alanine, MESH: Cross-Linking Reagents, Microbial Sensitivity Tests, Peptidoglycan, Biology, beta-Lactams, Models, Biological, Article, 03 medical and health sciences, MESH : Amino Acid Substitution, MESH : beta-Lactams, MESH : Hydrolysis, MESH: beta-Lactams, MESH: Anti-Bacterial Agents, Glycosyltransferase, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Glycopeptides, 030306 microbiology, MESH: Cytoplasm, MESH : Peptide Fragments, MESH: Models, Biological, Cell Biology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Peptide Fragments, chemistry, Amino Acid Substitution, biology.protein, MESH: Substrate Specificity, MESH : Microbial Sensitivity Tests, MESH : Alanine, Bacteria
Abstract: International audience; Glycopeptides and beta-lactams are the major antibiotics available for the treatment of infections due to Gram-positive bacteria. Emergence of cross-resistance to these drugs by a single mechanism has been considered as unlikely because they inhibit peptidoglycan polymerization by different mechanisms. The glycopeptides bind to the peptidyl-D-Ala(4)-D-Ala(5) extremity of peptidoglycan precursors and block by steric hindrance the essential glycosyltransferase and D,D-transpeptidase activities of the penicillin-binding proteins (PBPs). The beta-lactams are structural analogues of D-Ala(4)-D-Ala(5) and act as suicide substrates of the D,D-transpeptidase module of the PBPs. Here we have shown that bypass of the PBPs by the recently described beta-lactam-insensitive L,D-transpeptidase from Enterococcus faecium (Ldt(fm)) can lead to high level resistance to glycopeptides and beta-lactams. Cross-resistance was selected by glycopeptides alone or serially by beta-lactams and glycopeptides. In the corresponding mutants, UDP-MurNAc-pentapeptide was extensively converted to UDP-MurNAc-tetrapeptide following hydrolysis of D-Ala(5), thereby providing the substrate of Ldt(fm). Complete elimination of D-Ala(5), a residue essential for glycopeptide binding, was possible because Ldt(fm) uses the energy of the L-Lys(3)-D-Ala(4) peptide bond for cross-link formation in contrast to PBPs, which use the energy of the D-Ala(4)-D-Ala(5) bond. This novel mechanism of glycopeptide resistance was unrelated to the previously identified replacement of D-Ala(5) by D-Ser or D-lactate.
Published: 2006

11. Functional analysis of AtlA, the major N-acetylglucosaminidase of Enterococcus faecalis

Author: Catherine Eckert, Michel Arthur, Maxime Lecerf, Stéphane Mesnage, Lionel Dubost, Lecerf, Maxime, Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Chimie et Biochimie des Substances Naturelles, and Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH : Escherichia coli, MESH: Acetylglucosaminidase, medicine.disease_cause, law.invention, MESH: Recombinant Proteins, chemistry.chemical_compound, law, Tandem Mass Spectrometry, Enterococcus faecalis, MESH : Bacterial Proteins, Threonine, MESH : Enterococcus faecalis, MESH: Bacterial Proteins, MESH : Peptidoglycan, 0303 health sciences, medicine.diagnostic_test, MESH: Escherichia coli, MESH: Peptidoglycan, Recombinant Proteins, Biochemistry, Recombinant DNA, MESH : Tandem Mass Spectrometry, MESH: Enterococcus faecalis, MESH : Recombinant Proteins, Proteolysis, Peptidoglycan, Biology, Microbiology, 03 medical and health sciences, Bacterial Proteins, MESH : Acetylglucosaminidase, Acetylglucosaminidase, medicine, Escherichia coli, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Humans, 030306 microbiology, MESH : Humans, MESH: Tandem Mass Spectrometry, biology.organism_classification, Proteinase K, Molecular biology, Enzymes and Proteins, Enzyme assay, chemistry, biology.protein
Abstract: The major peptidoglycan hydrolase of Enterococcus faecalis , AtlA, has been identified, but its enzyme activity remains unknown. We have used tandem mass spectrometry analysis of peptidoglycan hydrolysis products obtained using the purified protein to show that AtlA is an N -acetylglucosaminidase. To gain insight into the regulation of its enzyme activity, the three domains of AtlA were purified alone or in combination following expression of truncated forms of the atlA gene in Escherichia coli or partial digestion of AtlA by proteinase K. The central domain of AtlA was catalytically active, but its activity was more than two orders of magnitude lower than that of the complete protein. Partial proteolysis of AtlA was detected in vivo: zymograms of E. faecalis extracts revealed two catalytically active protein bands of 62 and 72 kDa that were both absent in extracts from an atlA null mutant. Limited digestion of AtlA by proteinase K in vitro suggested that the proteolytic cleavage of AtlA in E. faecalis extracts corresponds to the truncation of the N-terminal domain, which is rich in threonine and glutamic acid residues. We show that the truncation of the N-terminal domain from recombinant AtlA has no impact on enzyme activity. The C-terminal domain of the protein, which contains six LysM modules bound to highly purified peptidoglycan, was required for optimal enzyme activity. These data indicate that AtlA is not produced as a proenzyme and that control of the AtlA glucosaminidase activity is likely to occur at the level of LysM-mediated binding to peptidoglycan.
Published: 2006

12. Ionpair-π interactions favor cell penetration of arginine/tryptophan-rich cell-penetrating peptides

Author: Astrid Walrant, Natpasit Chaianantakul, Isabel D. Alves, Françoise Illien, Antonio Frontera, Sandrine Sagan, Sophie Lecomte, Sébastien Cardon, Manjula Pallerla, Claudia Girardet, Antonio Bauzá, Fabienne Burlina, University of Cambridge [UK] (CAM), Departament de Quimica, Universitat des Illes Balears, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitat de les Illes Balears (UIB), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Naresuan University, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Chinese Hamster Ovary, Isothermal Titration Calorimetry, Arginine, CHO, [SDV]Life Sciences [q-bio], POPG, Peptide, Cell-Penetrating Peptides, Attenuated Total Reflection Fourier Transformed Infra Red, 01 natural sciences, Biochemistry, DFT, DSC, Cell membrane, Cricetinae, Lipid membrane, Lipid bilayer, Internalization, Glycosaminoglycans, media_common, Cell-penetrating-peptide, chemistry.chemical_classification, GAG, 0303 health sciences, cell-penetrating-peptide / ionpair-pi interaction / glycosaminoglycan / lipid membrane / tryptophan / arginine Abbreviations ART-FTIR, Differential Scanning Calorimetry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Tryptophan, [CHIM.MATE]Chemical Sciences/Material chemistry, Endocytosis, Protein Transport, Membrane, medicine.anatomical_structure, Thermodynamics, DMPG, media_common.quotation_subject, 1-palmitoyl-2, Biophysics, CHO Cells, 010402 general chemistry, Cell-Penetrating Peptide, 03 medical and health sciences, Cricetulus, medicine, Animals, Humans, Amino Acid Sequence, 030304 developmental biology, Ionpair-pi interaction, Cell Membrane, Isothermal titration calorimetry, Cell Biology, ITC, 0104 chemical sciences, 030104 developmental biology, Glycosaminoglycan, Cell-penetrating peptide, Density functional theory, CPP, 2-dimyristoyl sn-glycero-3-phospho-(1'-rac- glycerol)
Abstract: Cell-penetrating peptides (CPPs) internalization can occur both by endocytosis and direct translocation through the cell membrane. These different entry routes suggest that molecular partners at the plasma membrane, phospholipids or glycosaminoglycans (GAGs), bind CPPs with different affinity or selectivity. The analysis of sequence-dependent interactions of CPPs with lipids and GAGs should lead to a better understanding of the molecular mechanisms underlying their internalization. CPPs are short sequences generally containing a high number of basic arginines and lysines and sometimes aromatic residues, in particular tryptophans. Tryptophans are crucial residues in membrane-active peptides, because they are important for membrane interaction. Membrane-active peptides often present facial amphiphilicity, which also promote the interaction with lipid bilayers. To study the role of Trp and facial amphiphilicity in cell interaction and penetration of CPPs, a nonapeptide series containing only Arg, Trp or D-Trp residues at different positions was designed. Our quantitative study indicates that to maintain/increase the uptake efficiency, Arg can be advantageously replaced by Trp in the nonapeptides. The presence of Trp in oligoarginines increases the uptake in cells expressing GAGs at their surface, when it only compensates for the loss of Arg and maintains similar peptide uptake in GAG-deficient cells. In addition, we show that facial amphiphilicity is not required for efficient uptake of these nonapeptides. Thermodynamic analyses point towards a key role of Trp that highly contributes to the binding enthalpy of complexes formation. Density functional theory (DFT) analysis highlights that salt bridge-π interactions play a crucial role for the GAG-dependent entry mechanisms.
Published: 2019

13. Idiosyncratic features in tRNAs participating in bacterial cell wall synthesis

Author: Nathalie Josseaume, Lionel Dubost, Claudine Mayer, Jean-Marc Valery, Jean-Emmanuel Hugonnet, Stéphane Mesnage, Mélanie Etheve-Quelquejeu, Maryline Chemama, Michel Arthur, Antoine P. Maillard, Matthieu Fonvielle, Patricia Busca, Arul Marie, Régis Villet, Structure bactérienne et résistance aux antibiotiques (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse bactérienne et réponses cellulaires (PBRC), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Krebs Inst, University of Sheffield [Sheffield], Université Paris Diderot - Paris 7 (UPD7), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et Biochimie des Substances Naturelles, Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Base pair, [SDV]Life Sciences [q-bio], Molecular Sequence Data, RNA, Transfer, Ala, Peptidoglycan, Wobble base pair, MESH: Base Sequence, Biology, 03 medical and health sciences, chemistry.chemical_compound, MESH: Cell Wall, Cell Wall, Genetics, Transferase, Nucleotide, Peptide Synthases, MESH: RNA, Transfer, Ala, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Molecular Sequence Data, Bacteria, Base Sequence, Nucleic Acid Enzymes, MESH: Peptidoglycan, 030306 microbiology, Mutagenesis, MESH: Peptide Synthases, Amino acid, MESH: Bacteria, MESH: Mutagenesis, Site-Directed, chemistry, Biochemistry, Transfer RNA, Mutagenesis, Site-Directed, MESH: Uridine Diphosphate N-Acetylmuramic Acid, MESH: Models, Molecular
Abstract: International audience; The FemX(Wv) aminoacyl transferase of Weissella viridescens initiates the synthesis of the side chain of peptidoglycan precursors by transferring l-Ala from Ala-tRNA(Ala) to UDP-MurNAc-pentadepsipeptide. FemX(Wv) is an attractive target for the development of novel antibiotics, since the side chain is essential for the last cross-linking step of peptidoglycan synthesis. Here, we show that FemX(Wv) is highly specific for incorporation of l-Ala in vivo based on extensive analysis of the structure of peptidoglycan. Comparison of various natural and in vitro-transcribed tRNAs indicated that the specificity of FemX(Wv) depends mainly upon the sequence of the tRNA although additional specificity determinants may include post-transcriptional modifications and recognition of the esterified amino acid. Site-directed mutagenesis identified cytosines in the G1-C72 and G2-C71 base pairs of the acceptor stem as critical for FemX(Wv) activity in agreement with modeling of tRNA(Ala) in the catalytic cavity of the enzyme. In contrast, semi-synthesis of Ala-tRNA(Ala) harboring nucleotide substitutions in the G3-U70 wobble base pair showed that this main identity determinant of alanyl-tRNA synthetase is non-essential for FemX(Wv). The different modes of recognition of the acceptor stem indicate that specific inhibition of FemX(Wv) could be achieved by targeting the distal portion of tRNA(Ala) for the design of substrate analogues.
Published: 2007

14. Genome wide association study identifies KCNMA1contributing to human obesity

Author: David Brodin, Anders Hamsten, Ferdinand M. van't Hooft, Ingrid Dahlman, Sébastien Czernichow, Thorkild I. A. Sørensen, Oluf Pedersen, Hong Jiao, Torben Hansen, Tomas Axelsson, Johan Hoffstedt, Johannes Hebebrand, Peter Arner, Karin Dahlman-Wright, Juha Kere, Béatrice Dubern, Karine Clément, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Clinical Research Centre, Karolinska University Hospital [Stockholm], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cardiovascular Genetics Group, Karolinska Institutet [Stockholm]-Atherosclerosis Research Unit-Department of Medicine Solna, Department of Medical Sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, Hagedorn Research Institute, Gentofte, Center of Basic Metabolic Research, Faculty of Health Sciences-University of Copenhagen ( KU ), Institute for Preventive Medicine, Copenhagen University Hospital-Center for Health and Society, Department of Child and Adolescent Psychiatry, Universität Duisburg-Essen [Essen], Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), This project was supported by grants from AFA (PA), the Swedish Heart and Lung Foundation (PA, AHA), the Swedish Research Council (PA, AHA, ID), Novo Nordic Foundation (ID), Swedish Diabetes Association (PA), the Knut and Alice Wallenberg Foundation and the Stockholm County Council (project 56218, AHA)., Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], and Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Medizin, Genome-wide association study, Susceptibility Locus, Bioinformatics, FTO gene, Body Mass Index, Cohort Studies, 0302 clinical medicine, Germany, ADULT OBESITY, EXTREME OBESITY, Genetics(clinical), Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Genetics (clinical), 2. Zero hunger, 0303 health sciences, education.field_of_study, Obesity Gene, Allelic Association, COMMON VARIANTS, Middle Aged, Obesity, Morbid, FAT MASS, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, France, CHILDHOOD OBESITY, METABOLIC TRAITS, Research Article, medicine.medical_specialty, lcsh:Internal medicine, NON-REPLICATION, lcsh:QH426-470, Population, EARLY-ONSET, BODY-MASS INDEX, FTO GENE, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Childhood obesity, 03 medical and health sciences, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Genetics, ddc:61, Humans, Genetic Predisposition to Disease, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Obesity, education, lcsh:RC31-1245, Alleles, 030304 developmental biology, Sweden, Genome, Human, Odds ratio, medicine.disease, Morbid Obesity, lcsh:Genetics, Endocrinology, Case-Control Studies, Body mass index, Genome-Wide Association Study
Abstract: Background Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m2) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults. Results Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 × 10-10 and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 × 10-17and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
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15. Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case-control study

Author: Sébastien Czernichow, J Le Beyec, Karine Clément, F Bellisle, M Valette, Christine Poitou, Claire Carette, Serge Hercberg, Emmanuelle Kesse-Guyot, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine, Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), foundation NRJ- Institute de France and Programme Hospitalier de Recherche Clinique (APHP), University Paris 13, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Leptin, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Receptors, Cell Surface, eating disorders, Gene mutation, eating behavior, medicine.disease_cause, Body Mass Index, Eating, 03 medical and health sciences, 0302 clinical medicine, binge eating, Surveys and Questionnaires, Internal medicine, MC4R mutations, medicine, Humans, Obesity, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Mutation, Nutrition and Dietetics, melanocortin-4 receptor, Binge eating, business.industry, Case-control study, Feeding Behavior, Middle Aged, 3. Good health, Melanocortin 4 receptor, Endocrinology, Case-Control Studies, Receptor, Melanocortin, Type 4, Female, Melanocortin, medicine.symptom, Energy Intake, business, Body mass index, 030217 neurology & neurosurgery, Dietary Carbohydrates
Abstract: International audience; Melanocortin-4 receptor (MC4R) gene mutations are involved in the leptin-melanocortin pathways that control food intake. The effect of these mutations on eating behavior phenotypes is still debated. To determine the association between functional MC4R mutations and eating behaviors, dietary intake and physical activity, we sequenced the MC4R gene in 4653 obese adults. Among them, 19 adults carriers of functional MC4R mutation were matched on age, sex and body mass index with two randomly-paired controls without MC4R mutation (n = 57). We found that eating behaviors and physical activity did not differ between groups. In particular, cases were not at increased risk of binge eating disorders. Subjects carriers of MC4R mutation reported a higher proportion of dietary carbohydrates intakes (43.2 +/- 7.1 and 39.2 +/- 8.1% of total energy intake, respectively, P = 0.048) and a lower proportion of dietary lipids (34.3 +/- 6.7 and 38.5 +/- 6.7% of total energy intake, respectively, P = 0.018). In conclusion, mutation carriers differ from controls by a higher consumption of carbohydrates counterbalanced by a lower consumption of lipids expressed as percentage of total energy intake. However, functional MC4R mutations do not have a higher risk of compulsive eating contrary to what was previously suggested.
Published: 2014

16. Melanocortin-4 Receptor Mutations and Polymorphisms Do Not Affect Weight Loss after Bariatric Surgery

Author: Karine Clément, Johanne Le Beyec, Marion Valette, Christine Poitou, Jean-Luc Bouillot, Sébastien Czernichow, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), foundation NRJ - Institute de France, University Paris 13, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ProdInra, Migration
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], lcsh:Medicine, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Clinical nutrition, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Weight loss, medicine, SNP, lcsh:Science, 030304 developmental biology, 0303 health sciences, Mutation, Multidisciplinary, lcsh:R, Case-control study, medicine.disease, Obesity, 3. Good health, Surgery, [SDV] Life Sciences [q-bio], Melanocortin 4 receptor, lcsh:Q, medicine.symptom
Abstract: International audience; Bariatric surgery is the most effective long term weight-loss therapy for severe and morbidly obese patients. Melanocortin-4 Receptor (MC4R) mutations, the most frequent known cause of monogenic obesity, affect the regulation of energy homeostasis. The impact of such mutations on weight loss after bariatric surgery is still debated. The objective is to determine the impact of MC4R status on weight loss in obese subjects over one year after bariatric surgery. A total of 648 patients, who were referred to bariatric surgery in a single clinical nutrition department, were genotyped for their MC4R status. The following four groups were categorized: functional MC4R mutations, MC4R single nucleotide polymorphisms (SNPs): Val103Ile (V103L) and Ile251Leu (I251L), MC4R variant rs17782313 (downstream of MC4R) and MC4R SNP A-178C on the promoter. Each patient was matched with two randomly paired controls without mutation. Matching factors were age, sex, baseline weight and type of surgery procedure (Roux-en-Y gastric bypass and adjustable gastric banding). We compared weight loss between cases and controls at 3, 6 and 12 months after surgery. Among 648 patients, we identified 9 carriers of functional MC4R mutations, 10 carriers of MC4R V103L and I251L SNPs, 7 carriers of the rs17792313 variant and 22 carriers of the A-178C SNP. Weight loss at 3, 6 and 12 months did not differ between cases and controls, whatever the MC4R mutations. This is the first case-control study to show that MC4R mutations and polymorphisms do not affect weight loss and body composition over one year after bariatric surgery.
Published: 2012

17. Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity

Author: Monica Mencarelli, Patrick Tounian, Anna Maria Di Blasio, Chantal Simon, Serge Hercberg, Lina Benajiba, Béatrice Dubern, Pilar Galan, Antonio Liuzzi, Mariantonella Tagliaferri, Maura Rinaldi, Rohia Alili, Karine Clément, Sabrina Maestrini, Mol Biol Lab, Brazilian Agricultural Research Corporation (Embrapa), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Istituto Auxologico Italiano, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Université Paris Nord (Paris 13), Mécanisme Moléculaire du Diabète (MMD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), Ile de France, Institut Benjamin Delessert and Guigoz, Paris, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, [SDV]Life Sciences [q-bio], CHILDREN, MC4R, medicine.disease_cause, 0302 clinical medicine, Child, Genetics (clinical), Genetics, 0303 health sciences, Mutation, General Medicine, Middle Aged, Phenotype, Melanocortin 3 receptor, 3. Good health, PREVALENCE, Melanocortin 4 receptor, FAT MASS, Receptor, Melanocortin, Type 4, Female, GENE VARIANTS, medicine.symptom, Receptor, Melanocortin, Type 3, Adult, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, Biology, White People, Young Adult, 03 medical and health sciences, EARLY-ONSET OBESITY, Melanocortin receptor, Internal medicine, medicine, Humans, Obesity, Molecular Biology, Gene, POLYMORPHISMS, 030304 developmental biology, FRAMESHIFT MUTATION, Body Weight, medicine.disease, BODY-MASS INDEX, HEK293 Cells, Endocrinology, INTRACELLULAR RETENTION, Weight gain
Abstract: International audience; In contrast to the melanocortin 4 receptor, the possible role of the melanocortin 3 receptor (MC3R) in regulating body weight is still debated. We have previously reported three mutations in the MC3R gene showing association with human obesity, but these results were not confirmed in a study of severe obese North American adults. In this study, we evaluated the entire coding region of MC3R in 839 severely obese subjects and 967 lean controls of Italian and French origin. In vitro functional analysis of the mutations detected was also performed. The total prevalence of rare MC3R variants was not significantly different in obese subjects when compared with controls (P = 0.18). However, the prevalence of mutations with functional alterations was significantly higher in the obese group (P = 0.022). In conclusions, the results of this large study demonstrate that in the populations studied functionally significant MC3R variants are associated with obesity supporting the current hypothesis that rare variants might have a stronger impact on the individual susceptibility to gain weight. They also underline the importance of detailed in vitro functional studies in order to prove the pathogenic effect of such variants. Further investigations in larger cohorts will be needed in order to define the specific phenotypic characteristics potentially correlated with reduced MC3R signalling
Published: 2011

18. Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation

Author: Sophie Layé, Karine Clément, A. Basdevant, V Frochot, D. Machaux-Tholliez, C. Poitou, Lucile Capuron, Jean-Luc Bouillot, Nutrition et Neurobiologie intégrée (NutriNeuro), Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structures bactériennes impliquées dans la modulation de la résistance aux antibiotiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Neurotic Disorders, [SDV]Life Sciences [q-bio], Adipokine, Bariatric Surgery, Body Mass Index, Extraversion, Psychological, 03 medical and health sciences, 0302 clinical medicine, Adipokines, Weight loss, Diabetes mellitus, Internal medicine, Surveys and Questionnaires, medicine, Humans, Affective Symptoms, Applied Psychology, 030304 developmental biology, Adiposity, 2. Zero hunger, Inflammation, Psychiatric Status Rating Scales, 0303 health sciences, biology, business.industry, Interleukin-6, C-reactive protein, Feeding Behavior, Middle Aged, medicine.disease, Neuroticism, Obesity, Obesity, Morbid, Psychiatry and Mental health, Endocrinology, C-Reactive Protein, biology.protein, Anxiety, Female, medicine.symptom, business, Body mass index, 030217 neurology & neurosurgery, Biomarkers, Follow-Up Studies
Abstract: BackgroundObesity is characterized by chronic low-grade inflammation that may lead to emotional distress and behavioural symptoms. This study assessed the relationship between adiposity, low-grade inflammation, eating behaviour and emotional status in obese women awaiting gastric surgery and investigated the effects of surgery-induced weight loss on this relationship.MethodA total of 101 women with severe or morbid obesity awaiting gastric surgery were recruited. Assessments were performed before and at 1 year post-surgery and included the measurement of neuroticism and extraversion using the revised Neuroticism–Extraversion–Openness personality inventory (NEO-PI-R) and eating behaviour using the Three-Factor Eating Questionnaire (TFEQ). Blood samples were collected for the measurement of serum inflammatory markers [interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP)] and adipokines (leptin, adiponectin).ResultsAt baseline, body mass index (BMI) was positively correlated with inflammatory markers and adipokines. Regression analyses adjusting for age and diabetes revealed that baseline concentrations of IL-6 and hsCRP were associated with the depression and anxiety facets of neuroticism, with higher inflammation predicting higher anxiety and depression. This association remained significant after adjusting for BMI. Gastric surgery induced significant weight loss, which correlated with reduced inflammation. After controlling for BMI variations, decreases in inflammatory markers, notably hsCRP, were associated with reduced anxiety and TFEQ-cognitive restraint scores.ConclusionsThese findings indicate strong associations between adiposity, inflammation and affectivity in obese subjects and show that surgery-induced weight loss is associated concomitantly with reduced inflammation and adipokines and with significant improvement in emotional status and eating behaviour. Inflammatory status appears to represent an important mediator of emotional distress and psychological characteristics of obese individuals.
Published: 2010

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18 results on '"Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

1. Association of the Pro12Ala and C1431T Variants ofPPARγ and Their Haplotypes with Susceptibility to Gestational Diabetes

2. Serine/threonine protein phosphatase-mediated control of the peptidoglycan cross-linking L,D-transpeptidase pathway in Enterococcus faecium

3. Specificity determinants for the two tRNA substrates of the cyclodipeptide synthase AlbC from Streptomyces noursei

4. Colicin M, a peptidoglycan lipid-II-degrading enzyme: potential use for antibacterial means?

5. Characterization of colicin M and its orthologs targeting bacterial cell wall peptidoglycan biosynthesis

6. Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance

7. Identification of the L,D-transpeptidases responsible for attachment of the Braun lipoprotein to Escherichia coli peptidoglycan

8. Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes

9. The Enterococcus hirae Mur-2 enzyme displays N-acetylglucosaminidase activity

10. Novel mechanism of resistance to glycopeptide antibiotics in Enterococcus faecium

11. Functional analysis of AtlA, the major N-acetylglucosaminidase of Enterococcus faecalis

12. Ionpair-π interactions favor cell penetration of arginine/tryptophan-rich cell-penetrating peptides

13. Idiosyncratic features in tRNAs participating in bacterial cell wall synthesis

14. Genome wide association study identifies KCNMA1contributing to human obesity

15. Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case-control study

16. Melanocortin-4 Receptor Mutations and Polymorphisms Do Not Affect Weight Loss after Bariatric Surgery

17. Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity

18. Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation

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