The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis.
Identifieur interne : 000301 ( Main/Exploration ); précédent : 000300; suivant : 000302The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis.
Auteurs : Leonardo Astolfi Rosado [Belgique] ; Khadija Wahni [Belgique] ; Giulia Degiacomi ; Brandán Pedre [Belgique] ; David Young [Belgique] ; Alfonso G. De La Rubia [Espagne] ; Francesca Boldrin ; Edo Martens [Belgique] ; Laura Marcos-Pascual [Espagne] ; Enea Sancho-Vaello [Espagne] ; David Albesa-Jové [Espagne] ; Roberta Provvedi [Italie] ; Charlotte Martin [Belgique] ; Vadim Makarov [Russie] ; Wim Versées [Belgique] ; Guido Verniest [Belgique] ; Marcelo E. Guerin [Espagne] ; Luis M. Mateos [Espagne] ; Riccardo Manganelli [Italie] ; Joris Messens [Belgique]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2017.
Descripteurs français
- KwdFr :
- Activation métabolique (MeSH), Antibactériens (composition chimique), Antibactériens (métabolisme), Antibactériens (pharmacologie), Biocatalyse (MeSH), Conformation des protéines (MeSH), Conformation moléculaire (MeSH), Cristallographie aux rayons X (MeSH), Cystéine (métabolisme), Domaine catalytique (MeSH), Délétion de gène (MeSH), Modèles moléculaires (MeSH), Mycobacterium tuberculosis (croissance et développement), Mycobacterium tuberculosis (effets des médicaments et des substances chimiques), Mycobacterium tuberculosis (enzymologie), Médicaments en essais cliniques (composition chimique), Médicaments en essais cliniques (métabolisme), Médicaments en essais cliniques (pharmacologie), Oxydoréduction (MeSH), Phylogenèse (MeSH), Promédicaments (composition chimique), Promédicaments (métabolisme), Promédicaments (pharmacologie), Protein Disulfide-Isomerases (composition chimique), Protein Disulfide-Isomerases (génétique), Protein Disulfide-Isomerases (métabolisme), Protéines bactériennes (composition chimique), Protéines bactériennes (génétique), Protéines bactériennes (métabolisme), Protéines recombinantes (métabolisme), Pyrimidines (composition chimique), Pyrimidines (métabolisme), Pyrimidines (pharmacologie), Simulation de docking moléculaire (MeSH), Spécificité du substrat (MeSH), Stress oxydatif (effets des médicaments et des substances chimiques), Tests d'agents antimicrobiens par diffusion à partir de disques (MeSH).
- MESH :
- composition chimique : Antibactériens, Médicaments en essais cliniques, Promédicaments, Protein Disulfide-Isomerases, Protéines bactériennes, Pyrimidines.
- croissance et développement : Mycobacterium tuberculosis.
- effets des médicaments et des substances chimiques : Mycobacterium tuberculosis, Stress oxydatif.
- enzymologie : Mycobacterium tuberculosis.
- génétique : Protein Disulfide-Isomerases, Protéines bactériennes.
- métabolisme : Antibactériens, Cystéine, Médicaments en essais cliniques, Promédicaments, Protein Disulfide-Isomerases, Protéines bactériennes, Protéines recombinantes, Pyrimidines.
- pharmacologie : Antibactériens, Médicaments en essais cliniques, Promédicaments, Pyrimidines.
- Activation métabolique, Biocatalyse, Conformation des protéines, Conformation moléculaire, Cristallographie aux rayons X, Domaine catalytique, Délétion de gène, Modèles moléculaires, Oxydoréduction, Phylogenèse, Simulation de docking moléculaire, Spécificité du substrat, Tests d'agents antimicrobiens par diffusion à partir de disques.
English descriptors
- KwdEn :
- Activation, Metabolic (MeSH), Anti-Bacterial Agents (chemistry), Anti-Bacterial Agents (metabolism), Anti-Bacterial Agents (pharmacology), Bacterial Proteins (chemistry), Bacterial Proteins (genetics), Bacterial Proteins (metabolism), Biocatalysis (MeSH), Catalytic Domain (MeSH), Crystallography, X-Ray (MeSH), Cysteine (metabolism), Disk Diffusion Antimicrobial Tests (MeSH), Drugs, Investigational (chemistry), Drugs, Investigational (metabolism), Drugs, Investigational (pharmacology), Gene Deletion (MeSH), Models, Molecular (MeSH), Molecular Conformation (MeSH), Molecular Docking Simulation (MeSH), Mycobacterium tuberculosis (drug effects), Mycobacterium tuberculosis (enzymology), Mycobacterium tuberculosis (growth & development), Oxidation-Reduction (MeSH), Oxidative Stress (drug effects), Phylogeny (MeSH), Prodrugs (chemistry), Prodrugs (metabolism), Prodrugs (pharmacology), Protein Conformation (MeSH), Protein Disulfide-Isomerases (chemistry), Protein Disulfide-Isomerases (genetics), Protein Disulfide-Isomerases (metabolism), Pyrimidines (chemistry), Pyrimidines (metabolism), Pyrimidines (pharmacology), Recombinant Proteins (metabolism), Substrate Specificity (MeSH).
- MESH :
- chemical , chemistry : Anti-Bacterial Agents, Bacterial Proteins, Drugs, Investigational, Prodrugs, Protein Disulfide-Isomerases, Pyrimidines.
- chemical , genetics : Bacterial Proteins, Protein Disulfide-Isomerases.
- chemical , metabolism : Anti-Bacterial Agents, Bacterial Proteins, Cysteine, Drugs, Investigational, Prodrugs, Protein Disulfide-Isomerases, Pyrimidines, Recombinant Proteins.
- chemical , pharmacology : Anti-Bacterial Agents, Drugs, Investigational, Prodrugs, Pyrimidines.
- drug effects : Mycobacterium tuberculosis, Oxidative Stress.
- enzymology : Mycobacterium tuberculosis.
- growth & development : Mycobacterium tuberculosis.
- Activation, Metabolic, Biocatalysis, Catalytic Domain, Crystallography, X-Ray, Disk Diffusion Antimicrobial Tests, Gene Deletion, Models, Molecular, Molecular Conformation, Molecular Docking Simulation, Oxidation-Reduction, Phylogeny, Protein Conformation, Substrate Specificity.
Abstract
The Mycobacterium tuberculosis rv2466c gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in M. tuberculosis have remained enigmatic. In this study, we report that Rv2466c is essential for bacterial survival under H2O2 stress. Further, we discovered that Rv2466c lacks oxidase activity; rather, it receives electrons through the mycothiol/mycothione reductase/NADPH pathway to activate TP053, preferentially via a dithiol-disulfide mechanism. We also found that Rv2466c uses a monothiol-disulfide exchange mechanism to reduce S-mycothiolated mixed disulfides and intramolecular disulfides. Genetic, phylogenetic, bioinformatics, structural, and biochemical analyses revealed that Rv2466c is a novel mycothiol-dependent reductase, which represents a mycoredoxin cluster of enzymes within the DsbA family different from the glutaredoxin cluster to which mycoredoxin-1 (Mrx1 or Rv3198A) belongs. To validate this DsbA-mycoredoxin cluster, we also characterized a homologous enzyme of Corynebacterium glutamicum (NCgl2339) and observed that it demycothiolates and reduces a mycothiol arsenate adduct with kinetic properties different from those of Mrx1. In conclusion, our work has uncovered a DsbA-like mycoredoxin that promotes mycobacterial resistance to oxidative stress and reacts with free mycothiol and mycothiolated targets. The characterization of the DsbA-like mycoredoxin cluster reported here now paves the way for correctly classifying similar enzymes from other organisms.
DOI: 10.1074/jbc.M117.797837
PubMed: 28620052
PubMed Central: PMC5555174
Affiliations:
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Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Marcos Pascual, Laura" sort="Marcos Pascual, Laura" uniqKey="Marcos Pascual L" first="Laura" last="Marcos-Pascual">Laura Marcos-Pascual</name><affiliation wicri:level="2"><nlm:affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León</wicri:regionArea><placeName><region nuts="2" type="communauté">Castille-et-León</region></placeName></affiliation></author><author><name sortKey="Sancho Vaello, Enea" sort="Sancho Vaello, Enea" uniqKey="Sancho Vaello E" first="Enea" last="Sancho-Vaello">Enea Sancho-Vaello</name><affiliation wicri:level="2"><nlm:affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation></author><author><name sortKey="Albesa Jove, David" sort="Albesa Jove, David" uniqKey="Albesa Jove D" first="David" last="Albesa-Jové">David Albesa-Jové</name><affiliation wicri:level="2"><nlm:affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation><nlm:affiliation>IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Provvedi, Roberta" sort="Provvedi, Roberta" uniqKey="Provvedi R" first="Roberta" last="Provvedi">Roberta Provvedi</name><affiliation wicri:level="1"><nlm:affiliation>Biology, University of Padova, 35121 Padova, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Biology, University of Padova, 35121 Padova</wicri:regionArea><wicri:noRegion>35121 Padova</wicri:noRegion></affiliation></author><author><name sortKey="Martin, Charlotte" sort="Martin, Charlotte" uniqKey="Martin C" first="Charlotte" last="Martin">Charlotte Martin</name><affiliation wicri:level="1"><nlm:affiliation>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation></author><author><name sortKey="Makarov, Vadim" sort="Makarov, Vadim" uniqKey="Makarov V" first="Vadim" last="Makarov">Vadim Makarov</name><affiliation wicri:level="1"><nlm:affiliation>the A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, 119071 Moscow, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>the A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, 119071 Moscow</wicri:regionArea><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Versees, Wim" sort="Versees, Wim" uniqKey="Versees W" first="Wim" last="Versées">Wim Versées</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Verniest, Guido" sort="Verniest, Guido" uniqKey="Verniest G" first="Guido" last="Verniest">Guido Verniest</name><affiliation wicri:level="1"><nlm:affiliation>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation></author><author><name sortKey="Guerin, Marcelo E" sort="Guerin, Marcelo E" uniqKey="Guerin M" first="Marcelo E" last="Guerin">Marcelo E. Guerin</name><affiliation wicri:level="2"><nlm:affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation><nlm:affiliation>IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Mateos, Luis M" sort="Mateos, Luis M" uniqKey="Mateos L" first="Luis M" last="Mateos">Luis M. Mateos</name><affiliation wicri:level="2"><nlm:affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León</wicri:regionArea><placeName><region nuts="2" type="communauté">Castille-et-León</region></placeName></affiliation></author><author><name sortKey="Manganelli, Riccardo" sort="Manganelli, Riccardo" uniqKey="Manganelli R" first="Riccardo" last="Manganelli">Riccardo Manganelli</name><affiliation wicri:level="1"><nlm:affiliation>the Departments of Molecular Medicine and riccardo.manganelli@unipd.it.</nlm:affiliation><country wicri:rule="url">Italie</country></affiliation></author><author><name sortKey="Messens, Joris" sort="Messens, Joris" uniqKey="Messens J" first="Joris" last="Messens">Joris Messens</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium, joris.messens@vib-vub.be.</nlm:affiliation><country wicri:rule="url">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium</wicri:regionArea><wicri:noRegion>Belgium</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28620052</idno><idno type="pmid">28620052</idno><idno type="doi">10.1074/jbc.M117.797837</idno><idno type="pmc">PMC5555174</idno><idno type="wicri:Area/Main/Corpus">000330</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000330</idno><idno type="wicri:Area/Main/Curation">000330</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000330</idno><idno type="wicri:Area/Main/Exploration">000330</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of <i>Mycobacterium tuberculosis</i>.</title><author><name sortKey="Rosado, Leonardo Astolfi" sort="Rosado, Leonardo Astolfi" uniqKey="Rosado L" first="Leonardo Astolfi" last="Rosado">Leonardo Astolfi Rosado</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Wahni, Khadija" sort="Wahni, Khadija" uniqKey="Wahni K" first="Khadija" last="Wahni">Khadija Wahni</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Degiacomi, Giulia" sort="Degiacomi, Giulia" uniqKey="Degiacomi G" first="Giulia" last="Degiacomi">Giulia Degiacomi</name><affiliation><nlm:affiliation>the Departments of Molecular Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">the Departments of Molecular Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Pedre, Brandan" sort="Pedre, Brandan" uniqKey="Pedre B" first="Brandán" last="Pedre">Brandán Pedre</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Young, David" sort="Young, David" uniqKey="Young D" first="David" last="Young">David Young</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="De La Rubia, Alfonso G" sort="De La Rubia, Alfonso G" uniqKey="De La Rubia A" first="Alfonso G" last="De La Rubia">Alfonso G. De La Rubia</name><affiliation wicri:level="2"><nlm:affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León</wicri:regionArea><placeName><region nuts="2" type="communauté">Castille-et-León</region></placeName></affiliation></author><author><name sortKey="Boldrin, Francesca" sort="Boldrin, Francesca" uniqKey="Boldrin F" first="Francesca" last="Boldrin">Francesca Boldrin</name><affiliation><nlm:affiliation>the Departments of Molecular Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">the Departments of Molecular Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Martens, Edo" sort="Martens, Edo" uniqKey="Martens E" first="Edo" last="Martens">Edo Martens</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Marcos Pascual, Laura" sort="Marcos Pascual, Laura" uniqKey="Marcos Pascual L" first="Laura" last="Marcos-Pascual">Laura Marcos-Pascual</name><affiliation wicri:level="2"><nlm:affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León</wicri:regionArea><placeName><region nuts="2" type="communauté">Castille-et-León</region></placeName></affiliation></author><author><name sortKey="Sancho Vaello, Enea" sort="Sancho Vaello, Enea" uniqKey="Sancho Vaello E" first="Enea" last="Sancho-Vaello">Enea Sancho-Vaello</name><affiliation wicri:level="2"><nlm:affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation></author><author><name sortKey="Albesa Jove, David" sort="Albesa Jove, David" uniqKey="Albesa Jove D" first="David" last="Albesa-Jové">David Albesa-Jové</name><affiliation wicri:level="2"><nlm:affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation><nlm:affiliation>IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Provvedi, Roberta" sort="Provvedi, Roberta" uniqKey="Provvedi R" first="Roberta" last="Provvedi">Roberta Provvedi</name><affiliation wicri:level="1"><nlm:affiliation>Biology, University of Padova, 35121 Padova, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Biology, University of Padova, 35121 Padova</wicri:regionArea><wicri:noRegion>35121 Padova</wicri:noRegion></affiliation></author><author><name sortKey="Martin, Charlotte" sort="Martin, Charlotte" uniqKey="Martin C" first="Charlotte" last="Martin">Charlotte Martin</name><affiliation wicri:level="1"><nlm:affiliation>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation></author><author><name sortKey="Makarov, Vadim" sort="Makarov, Vadim" uniqKey="Makarov V" first="Vadim" last="Makarov">Vadim Makarov</name><affiliation wicri:level="1"><nlm:affiliation>the A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, 119071 Moscow, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>the A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, 119071 Moscow</wicri:regionArea><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Versees, Wim" sort="Versees, Wim" uniqKey="Versees W" first="Wim" last="Versées">Wim Versées</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author><author><name sortKey="Verniest, Guido" sort="Verniest, Guido" uniqKey="Verniest G" first="Guido" last="Verniest">Guido Verniest</name><affiliation wicri:level="1"><nlm:affiliation>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation></author><author><name sortKey="Guerin, Marcelo E" sort="Guerin, Marcelo E" uniqKey="Guerin M" first="Marcelo E" last="Guerin">Marcelo E. Guerin</name><affiliation wicri:level="2"><nlm:affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio</wicri:regionArea><placeName><region nuts="2" type="communauté">Pays basque</region></placeName></affiliation><affiliation><nlm:affiliation>IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Mateos, Luis M" sort="Mateos, Luis M" uniqKey="Mateos L" first="Luis M" last="Mateos">Luis M. Mateos</name><affiliation wicri:level="2"><nlm:affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León</wicri:regionArea><placeName><region nuts="2" type="communauté">Castille-et-León</region></placeName></affiliation></author><author><name sortKey="Manganelli, Riccardo" sort="Manganelli, Riccardo" uniqKey="Manganelli R" first="Riccardo" last="Manganelli">Riccardo Manganelli</name><affiliation wicri:level="1"><nlm:affiliation>the Departments of Molecular Medicine and riccardo.manganelli@unipd.it.</nlm:affiliation><country wicri:rule="url">Italie</country></affiliation></author><author><name sortKey="Messens, Joris" sort="Messens, Joris" uniqKey="Messens J" first="Joris" last="Messens">Joris Messens</name><affiliation wicri:level="1"><nlm:affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium, joris.messens@vib-vub.be.</nlm:affiliation><country wicri:rule="url">Belgique</country><wicri:regionArea>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium</wicri:regionArea><wicri:noRegion>Belgium</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>the Brussels Center for Redox Biology, B-1050 Brussels</wicri:regionArea><wicri:noRegion>B-1050 Brussels</wicri:noRegion></affiliation><affiliation><nlm:affiliation>Structural Biology Brussels and.</nlm:affiliation><wicri:noCountry code="no comma">Structural Biology Brussels and.</wicri:noCountry></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Activation, Metabolic (MeSH)</term><term>Anti-Bacterial Agents (chemistry)</term><term>Anti-Bacterial Agents (metabolism)</term><term>Anti-Bacterial Agents (pharmacology)</term><term>Bacterial Proteins (chemistry)</term><term>Bacterial Proteins (genetics)</term><term>Bacterial Proteins (metabolism)</term><term>Biocatalysis (MeSH)</term><term>Catalytic Domain (MeSH)</term><term>Crystallography, X-Ray (MeSH)</term><term>Cysteine (metabolism)</term><term>Disk Diffusion Antimicrobial Tests (MeSH)</term><term>Drugs, Investigational (chemistry)</term><term>Drugs, Investigational (metabolism)</term><term>Drugs, Investigational (pharmacology)</term><term>Gene Deletion (MeSH)</term><term>Models, Molecular (MeSH)</term><term>Molecular Conformation (MeSH)</term><term>Molecular Docking Simulation (MeSH)</term><term>Mycobacterium tuberculosis (drug effects)</term><term>Mycobacterium tuberculosis (enzymology)</term><term>Mycobacterium tuberculosis (growth & development)</term><term>Oxidation-Reduction (MeSH)</term><term>Oxidative Stress (drug effects)</term><term>Phylogeny (MeSH)</term><term>Prodrugs (chemistry)</term><term>Prodrugs (metabolism)</term><term>Prodrugs (pharmacology)</term><term>Protein Conformation (MeSH)</term><term>Protein Disulfide-Isomerases (chemistry)</term><term>Protein Disulfide-Isomerases (genetics)</term><term>Protein Disulfide-Isomerases (metabolism)</term><term>Pyrimidines (chemistry)</term><term>Pyrimidines (metabolism)</term><term>Pyrimidines (pharmacology)</term><term>Recombinant Proteins (metabolism)</term><term>Substrate Specificity (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation métabolique (MeSH)</term><term>Antibactériens (composition chimique)</term><term>Antibactériens (métabolisme)</term><term>Antibactériens (pharmacologie)</term><term>Biocatalyse (MeSH)</term><term>Conformation des protéines (MeSH)</term><term>Conformation moléculaire (MeSH)</term><term>Cristallographie aux rayons X (MeSH)</term><term>Cystéine (métabolisme)</term><term>Domaine catalytique (MeSH)</term><term>Délétion de gène (MeSH)</term><term>Modèles moléculaires (MeSH)</term><term>Mycobacterium tuberculosis (croissance et développement)</term><term>Mycobacterium tuberculosis (effets des médicaments et des substances chimiques)</term><term>Mycobacterium tuberculosis (enzymologie)</term><term>Médicaments en essais cliniques (composition chimique)</term><term>Médicaments en essais cliniques (métabolisme)</term><term>Médicaments en essais cliniques (pharmacologie)</term><term>Oxydoréduction (MeSH)</term><term>Phylogenèse (MeSH)</term><term>Promédicaments (composition chimique)</term><term>Promédicaments (métabolisme)</term><term>Promédicaments (pharmacologie)</term><term>Protein Disulfide-Isomerases (composition chimique)</term><term>Protein Disulfide-Isomerases (génétique)</term><term>Protein Disulfide-Isomerases (métabolisme)</term><term>Protéines bactériennes (composition chimique)</term><term>Protéines bactériennes (génétique)</term><term>Protéines bactériennes (métabolisme)</term><term>Protéines recombinantes (métabolisme)</term><term>Pyrimidines (composition chimique)</term><term>Pyrimidines (métabolisme)</term><term>Pyrimidines (pharmacologie)</term><term>Simulation de docking moléculaire (MeSH)</term><term>Spécificité du substrat (MeSH)</term><term>Stress oxydatif (effets des médicaments et des substances chimiques)</term><term>Tests d'agents antimicrobiens par diffusion à partir de disques (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Bacterial Proteins</term><term>Drugs, Investigational</term><term>Prodrugs</term><term>Protein Disulfide-Isomerases</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Bacterial Proteins</term><term>Protein Disulfide-Isomerases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Bacterial Proteins</term><term>Cysteine</term><term>Drugs, Investigational</term><term>Prodrugs</term><term>Protein Disulfide-Isomerases</term><term>Pyrimidines</term><term>Recombinant Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Drugs, Investigational</term><term>Prodrugs</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antibactériens</term><term>Médicaments en essais cliniques</term><term>Promédicaments</term><term>Protein Disulfide-Isomerases</term><term>Protéines bactériennes</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Mycobacterium tuberculosis</term><term>Oxidative Stress</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Mycobacterium tuberculosis</term><term>Stress oxydatif</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protein Disulfide-Isomerases</term><term>Protéines bactériennes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antibactériens</term><term>Cystéine</term><term>Médicaments en essais cliniques</term><term>Promédicaments</term><term>Protein Disulfide-Isomerases</term><term>Protéines bactériennes</term><term>Protéines recombinantes</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antibactériens</term><term>Médicaments en essais cliniques</term><term>Promédicaments</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Activation, Metabolic</term><term>Biocatalysis</term><term>Catalytic Domain</term><term>Crystallography, X-Ray</term><term>Disk Diffusion Antimicrobial Tests</term><term>Gene Deletion</term><term>Models, Molecular</term><term>Molecular Conformation</term><term>Molecular Docking Simulation</term><term>Oxidation-Reduction</term><term>Phylogeny</term><term>Protein Conformation</term><term>Substrate Specificity</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation métabolique</term><term>Biocatalyse</term><term>Conformation des protéines</term><term>Conformation moléculaire</term><term>Cristallographie aux rayons X</term><term>Domaine catalytique</term><term>Délétion de gène</term><term>Modèles moléculaires</term><term>Oxydoréduction</term><term>Phylogenèse</term><term>Simulation de docking moléculaire</term><term>Spécificité du substrat</term><term>Tests d'agents antimicrobiens par diffusion à partir de disques</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The <i>Mycobacterium tuberculosis rv2466c</i> gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in <i>M. tuberculosis</i> have remained enigmatic. In this study, we report that Rv2466c is essential for bacterial survival under H<sub>2</sub>O<sub>2</sub> stress. Further, we discovered that Rv2466c lacks oxidase activity; rather, it receives electrons through the mycothiol/mycothione reductase/NADPH pathway to activate TP053, preferentially via a dithiol-disulfide mechanism. We also found that Rv2466c uses a monothiol-disulfide exchange mechanism to reduce <i>S</i>-mycothiolated mixed disulfides and intramolecular disulfides. Genetic, phylogenetic, bioinformatics, structural, and biochemical analyses revealed that Rv2466c is a novel mycothiol-dependent reductase, which represents a mycoredoxin cluster of enzymes within the DsbA family different from the glutaredoxin cluster to which mycoredoxin-1 (Mrx1 or Rv3198A) belongs. To validate this DsbA-mycoredoxin cluster, we also characterized a homologous enzyme of <i>Corynebacterium glutamicum</i> (NCgl2339) and observed that it demycothiolates and reduces a mycothiol arsenate adduct with kinetic properties different from those of Mrx1. In conclusion, our work has uncovered a DsbA-like mycoredoxin that promotes mycobacterial resistance to oxidative stress and reacts with free mycothiol and mycothiolated targets. The characterization of the DsbA-like mycoredoxin cluster reported here now paves the way for correctly classifying similar enzymes from other organisms.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28620052</PMID><DateCompleted><Year>2017</Year><Month>08</Month><Day>25</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1083-351X</ISSN><JournalIssue CitedMedium="Internet"><Volume>292</Volume><Issue>32</Issue><PubDate><Year>2017</Year><Month>08</Month><Day>11</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J Biol Chem</ISOAbbreviation></Journal><ArticleTitle>The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of <i>Mycobacterium tuberculosis</i>.</ArticleTitle><Pagination><MedlinePgn>13097-13110</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.M117.797837</ELocationID><Abstract><AbstractText>The <i>Mycobacterium tuberculosis rv2466c</i> gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in <i>M. tuberculosis</i> have remained enigmatic. In this study, we report that Rv2466c is essential for bacterial survival under H<sub>2</sub>O<sub>2</sub> stress. Further, we discovered that Rv2466c lacks oxidase activity; rather, it receives electrons through the mycothiol/mycothione reductase/NADPH pathway to activate TP053, preferentially via a dithiol-disulfide mechanism. We also found that Rv2466c uses a monothiol-disulfide exchange mechanism to reduce <i>S</i>-mycothiolated mixed disulfides and intramolecular disulfides. Genetic, phylogenetic, bioinformatics, structural, and biochemical analyses revealed that Rv2466c is a novel mycothiol-dependent reductase, which represents a mycoredoxin cluster of enzymes within the DsbA family different from the glutaredoxin cluster to which mycoredoxin-1 (Mrx1 or Rv3198A) belongs. To validate this DsbA-mycoredoxin cluster, we also characterized a homologous enzyme of <i>Corynebacterium glutamicum</i> (NCgl2339) and observed that it demycothiolates and reduces a mycothiol arsenate adduct with kinetic properties different from those of Mrx1. In conclusion, our work has uncovered a DsbA-like mycoredoxin that promotes mycobacterial resistance to oxidative stress and reacts with free mycothiol and mycothiolated targets. The characterization of the DsbA-like mycoredoxin cluster reported here now paves the way for correctly classifying similar enzymes from other organisms.</AbstractText><CopyrightInformation>© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rosado</LastName><ForeName>Leonardo Astolfi</ForeName><Initials>LA</Initials><Identifier Source="ORCID">0000-0002-4349-0244</Identifier><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wahni</LastName><ForeName>Khadija</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Degiacomi</LastName><ForeName>Giulia</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>the Departments of Molecular Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pedre</LastName><ForeName>Brandán</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Young</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>de la Rubia</LastName><ForeName>Alfonso G</ForeName><Initials>AG</Initials><AffiliationInfo><Affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boldrin</LastName><ForeName>Francesca</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>the Departments of Molecular Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martens</LastName><ForeName>Edo</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marcos-Pascual</LastName><ForeName>Laura</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sancho-Vaello</LastName><ForeName>Enea</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Albesa-Jové</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Provvedi</LastName><ForeName>Roberta</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Biology, University of Padova, 35121 Padova, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martin</LastName><ForeName>Charlotte</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Makarov</LastName><ForeName>Vadim</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>the A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, 119071 Moscow, Russia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Versées</LastName><ForeName>Wim</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Verniest</LastName><ForeName>Guido</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>the Research Group of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guerin</LastName><ForeName>Marcelo E</ForeName><Initials>ME</Initials><AffiliationInfo><Affiliation>the Unidad de Biofísica, Centro Mixto Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC, UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia 48940, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Departamento de Bioquímica, Universidad del País Vasco, Leioa, Bizkaia 48940, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mateos</LastName><ForeName>Luis M</ForeName><Initials>LM</Initials><AffiliationInfo><Affiliation>the Department of Molecular Biology, Area of Microbiology, University of León, 24071 León, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Manganelli</LastName><ForeName>Riccardo</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>the Departments of Molecular Medicine and riccardo.manganelli@unipd.it.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Messens</LastName><ForeName>Joris</ForeName><Initials>J</Initials><Identifier Source="ORCID">0000-0002-2128-8264</Identifier><AffiliationInfo><Affiliation>From the Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), B-1050 Brussels, Belgium, joris.messens@vib-vub.be.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>the Brussels Center for Redox Biology, B-1050 Brussels, Belgium.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Structural Biology Brussels and.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName><AccessionNumberList><AccessionNumber>4NXI</AccessionNumber></AccessionNumberList></DataBank></DataBankList><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>06</Month><Day>15</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000900">Anti-Bacterial Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001426">Bacterial Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015507">Drugs, Investigational</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011355">Prodrugs</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance 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MajorTopicYN="N">Bacterial Proteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055162" MajorTopicYN="N">Biocatalysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003545" MajorTopicYN="N">Cysteine</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D052978" MajorTopicYN="N">Disk Diffusion Antimicrobial Tests</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015507" MajorTopicYN="N">Drugs, Investigational</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017353" MajorTopicYN="N">Gene Deletion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="Y">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008968" MajorTopicYN="N">Molecular Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D062105" MajorTopicYN="N">Molecular Docking Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009169" MajorTopicYN="N">Mycobacterium tuberculosis</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName><QualifierName UI="Q000254" MajorTopicYN="N">growth & development</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010084" MajorTopicYN="N">Oxidation-Reduction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018384" MajorTopicYN="N">Oxidative Stress</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010802" MajorTopicYN="N">Phylogeny</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011355" MajorTopicYN="N">Prodrugs</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019704" MajorTopicYN="N">Protein Disulfide-Isomerases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011743" MajorTopicYN="N">Pyrimidines</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011994" MajorTopicYN="N">Recombinant Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013379" MajorTopicYN="N">Substrate Specificity</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Mycobacterium tuberculosis</Keyword><Keyword MajorTopicYN="Y">enzyme catalysis</Keyword><Keyword MajorTopicYN="Y">oxidation-reduction (redox)</Keyword><Keyword MajorTopicYN="Y">oxidative stress</Keyword><Keyword MajorTopicYN="Y">oxidoreductase</Keyword><Keyword MajorTopicYN="Y">phylogenetics</Keyword><Keyword MajorTopicYN="Y">thiol–disulfide exchange</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>05</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2017</Year><Month>06</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>6</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>8</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>6</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId 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basque</li></region><settlement><li>Moscou</li></settlement></list><tree><noCountry><name sortKey="Boldrin, Francesca" sort="Boldrin, Francesca" uniqKey="Boldrin F" first="Francesca" last="Boldrin">Francesca Boldrin</name><name sortKey="Degiacomi, Giulia" sort="Degiacomi, Giulia" uniqKey="Degiacomi G" first="Giulia" last="Degiacomi">Giulia Degiacomi</name></noCountry><country name="Belgique"><noRegion><name sortKey="Rosado, Leonardo Astolfi" sort="Rosado, Leonardo Astolfi" uniqKey="Rosado L" first="Leonardo Astolfi" last="Rosado">Leonardo Astolfi Rosado</name></noRegion><name sortKey="Martens, Edo" sort="Martens, Edo" uniqKey="Martens E" first="Edo" last="Martens">Edo Martens</name><name sortKey="Martens, Edo" sort="Martens, Edo" uniqKey="Martens E" first="Edo" last="Martens">Edo Martens</name><name sortKey="Martin, Charlotte" sort="Martin, Charlotte" uniqKey="Martin C" first="Charlotte" last="Martin">Charlotte Martin</name><name sortKey="Messens, Joris" sort="Messens, Joris" uniqKey="Messens J" first="Joris" last="Messens">Joris Messens</name><name sortKey="Messens, Joris" sort="Messens, Joris" uniqKey="Messens J" first="Joris" last="Messens">Joris Messens</name><name sortKey="Pedre, Brandan" sort="Pedre, Brandan" uniqKey="Pedre B" first="Brandán" last="Pedre">Brandán Pedre</name><name sortKey="Pedre, Brandan" sort="Pedre, Brandan" uniqKey="Pedre B" first="Brandán" last="Pedre">Brandán Pedre</name><name sortKey="Rosado, Leonardo Astolfi" sort="Rosado, Leonardo Astolfi" uniqKey="Rosado L" first="Leonardo Astolfi" last="Rosado">Leonardo Astolfi Rosado</name><name sortKey="Verniest, Guido" sort="Verniest, Guido" uniqKey="Verniest G" first="Guido" last="Verniest">Guido Verniest</name><name sortKey="Versees, Wim" sort="Versees, Wim" uniqKey="Versees W" first="Wim" last="Versées">Wim Versées</name><name sortKey="Wahni, Khadija" sort="Wahni, Khadija" uniqKey="Wahni K" first="Khadija" last="Wahni">Khadija Wahni</name><name sortKey="Wahni, Khadija" sort="Wahni, Khadija" uniqKey="Wahni K" first="Khadija" last="Wahni">Khadija Wahni</name><name sortKey="Young, David" sort="Young, David" uniqKey="Young D" first="David" last="Young">David Young</name><name sortKey="Young, David" sort="Young, David" uniqKey="Young D" first="David" last="Young">David Young</name></country><country name="Espagne"><region name="Castille-et-León"><name sortKey="De La Rubia, Alfonso G" sort="De La Rubia, Alfonso G" uniqKey="De La Rubia A" first="Alfonso G" last="De La Rubia">Alfonso G. De La Rubia</name></region><name sortKey="Albesa Jove, David" sort="Albesa Jove, David" uniqKey="Albesa Jove D" first="David" last="Albesa-Jové">David Albesa-Jové</name><name sortKey="Albesa Jove, David" sort="Albesa Jove, David" uniqKey="Albesa Jove D" first="David" last="Albesa-Jové">David Albesa-Jové</name><name sortKey="Albesa Jove, David" sort="Albesa Jove, David" uniqKey="Albesa Jove D" first="David" last="Albesa-Jové">David Albesa-Jové</name><name sortKey="Guerin, Marcelo E" sort="Guerin, Marcelo E" uniqKey="Guerin M" first="Marcelo E" last="Guerin">Marcelo E. Guerin</name><name sortKey="Guerin, Marcelo E" sort="Guerin, Marcelo E" uniqKey="Guerin M" first="Marcelo E" last="Guerin">Marcelo E. Guerin</name><name sortKey="Guerin, Marcelo E" sort="Guerin, Marcelo E" uniqKey="Guerin M" first="Marcelo E" last="Guerin">Marcelo E. Guerin</name><name sortKey="Marcos Pascual, Laura" sort="Marcos Pascual, Laura" uniqKey="Marcos Pascual L" first="Laura" last="Marcos-Pascual">Laura Marcos-Pascual</name><name sortKey="Mateos, Luis M" sort="Mateos, Luis M" uniqKey="Mateos L" first="Luis M" last="Mateos">Luis M. Mateos</name><name sortKey="Sancho Vaello, Enea" sort="Sancho Vaello, Enea" uniqKey="Sancho Vaello E" first="Enea" last="Sancho-Vaello">Enea Sancho-Vaello</name><name sortKey="Sancho Vaello, Enea" sort="Sancho Vaello, Enea" uniqKey="Sancho Vaello E" first="Enea" last="Sancho-Vaello">Enea Sancho-Vaello</name></country><country name="Italie"><noRegion><name sortKey="Provvedi, Roberta" sort="Provvedi, Roberta" uniqKey="Provvedi R" first="Roberta" last="Provvedi">Roberta Provvedi</name></noRegion><name sortKey="Manganelli, Riccardo" sort="Manganelli, Riccardo" uniqKey="Manganelli R" first="Riccardo" last="Manganelli">Riccardo Manganelli</name></country><country name="Russie"><region name="District fédéral central"><name sortKey="Makarov, Vadim" sort="Makarov, Vadim" uniqKey="Makarov V" first="Vadim" last="Makarov">Vadim Makarov</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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