Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infections

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dc.contributor.authorDrebes, Julia
dc.contributor.authorKünz, Madeleine
dc.contributor.authorWindshügel, Björn
dc.contributor.authorKikhney, Alexey G.
dc.contributor.authorMüller, Ingrid B.
dc.contributor.authorEberle, Raphael J. [UNESP]
dc.contributor.authorOberthür, Dominik
dc.contributor.authorCang, Huaixing
dc.contributor.authorSvergun, Dmitri I.
dc.contributor.authorPerbandt, Markus
dc.contributor.authorBetzel, Christian
dc.contributor.authorWrenger, Carsten
dc.contributor.institutionLaboratory for Structural Biology of Infection and Inflammation
dc.contributor.institutionBernhard Nocht Institute for Tropical Medicine
dc.contributor.institutionFraunhofer Institute for Molecular Biology and Applied Ecology (IME)
dc.contributor.institutionDESY
dc.contributor.institutionNorth Western Polytechnical University
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionHamburg Centre for Ultrafast Imaging
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionDeutsches Elektronen Synchrotron-DESY
dc.date.accessioned2018-12-11T16:41:27Z
dc.date.available2018-12-11T16:41:27Z
dc.date.issued2016-03-10
dc.description.abstractInfections caused by the methicillin-resistant Staphylococcus aureus (MRSA) are today known to be a substantial threat for global health. Emerging multi-drug resistant bacteria have created a substantial need to identify and discover new drug targets and to develop novel strategies to treat bacterial infections. A promising and so far untapped antibiotic target is the biosynthesis of vitamin B1 (thiamin). Thiamin in its activated form, thiamin pyrophosphate, is an essential co-factor for all organisms. Therefore, thiamin analogous compounds, when introduced into the vitamin B1 biosynthetic pathway and further converted into non-functional co-factors by the bacterium can function as pro-drugs which thus block various co-factor dependent pathways. We characterized one of the key enzymes within the S. aureus vitamin B1 biosynthetic pathway, 5-(hydroxyethyl)-4-methylthiazole kinase (SaThiM; EC 2.7.1.50), a potential target for pro-drug compounds and analyzed the native structure of SaThiM and complexes with the natural substrate 5-(hydroxyethyl)-4-methylthiazole (THZ) and two selected substrate analogues.en
dc.description.affiliationUniversity Hamburg DESY Laboratory for Structural Biology of Infection and Inflammation
dc.description.affiliationDepartment of Biochemistry Bernhard Nocht Institute for Tropical Medicine
dc.description.affiliationFraunhofer Institute for Molecular Biology and Applied Ecology (IME)
dc.description.affiliationEMBL Hamburg DESY
dc.description.affiliationSchool of Life Sciences North Western Polytechnical University
dc.description.affiliationUnit for Drug Discovery Department of Parasitology Institute of Biomedical Sciences University of São Paulo
dc.description.affiliationHamburg Centre for Ultrafast Imaging, Luruper Chaussee 149
dc.description.affiliationMultiuser Center for Biomolecular Innovation Department of Physics Universidade Estadual Paulista (UNESP)
dc.description.affiliationCenter for Free-Electron Laser Science Deutsches Elektronen Synchrotron-DESY, Notkestrasse 85
dc.description.affiliationUnespMultiuser Center for Biomolecular Innovation Department of Physics Universidade Estadual Paulista (UNESP)
dc.description.sponsorshipBundesministerium für Bildung und Forschung
dc.description.sponsorshipIdBundesministerium für Bildung und Forschung: 01DN13037
dc.description.sponsorshipIdBundesministerium für Bildung und Forschung: 50WB1017
dc.description.sponsorshipIdBundesministerium für Bildung und Forschung: WR124/2
dc.identifierhttp://dx.doi.org/10.1038/srep22871
dc.identifier.citationScientific Reports, v. 6.
dc.identifier.doi10.1038/srep22871
dc.identifier.file2-s2.0-84960911847.pdf
dc.identifier.issn2045-2322
dc.identifier.scopus2-s2.0-84960911847
dc.identifier.urihttp://hdl.handle.net/11449/168480
dc.language.isoeng
dc.relation.ispartofScientific Reports
dc.relation.ispartofsjr1,533
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.titleStructure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infectionsen
dc.typeArtigo

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