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dc.contributor.author
Santangelo, María de la Paz
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dc.contributor.author
Gest, Petra M.
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Guerin, Marcelo E.
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Coinçon, Mathieu
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Pham, Ha
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Ryan, Gavin
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Puckett, Susan E.
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Spencer, John S.
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Gonzalez Juarrero, Mercedes
dc.contributor.author
Daher, Racha
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Lenaerts, Anne J.
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Schnappinger, Dirk
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Therisod, Michel
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Ehrt, Sabine
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Sygusch, Jurgen
dc.contributor.author
Jackson, Mary
dc.date.available
2023-04-27T11:50:34Z
dc.date.issued
2011-11
dc.identifier.citation
Santangelo, María de la Paz; Gest, Petra M.; Guerin, Marcelo E.; Coinçon, Mathieu; Pham, Ha; et al.; Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 286; 46; 11-2011; 40219-40231
dc.identifier.issn
0021-9258
dc.identifier.uri
http://hdl.handle.net/11336/195594
dc.description.abstract
The search for antituberculosis drugs active against persistent bacilli has led to our interest in metallodependent class II fructose- 1,6-bisphosphate aldolase (FBA-tb), a key enzyme of gluconeogenesis absent from mammalian cells. Knock-out experiments at the fba-tb locus indicated that this gene is required for the growth of Mycobacterium tuberculosis on gluconeogenetic substrates and in glucose-containing medium. Surface labeling and enzymatic activity measurements revealed that this enzyme was exported to the cell surface of M. tuberculosis and produced under various axenic growth conditions including oxygen depletion and hence by non-replicating bacilli. Importantly, FBA-tb was also produced in vivo in the lungs of infected guinea pigs and mice. FBA-tb bound human plasmin(ogen) and protected FBA-tb-bound plasmin from regulation by α 2-antiplasmin, suggestive of an involvement of this enzyme in host/pathogen interactions. The crystal structures of FBA-tb in the native form and in complex with a hydroxamate substrate analog were determined to 2.35- and 1.9-Å resolution, respectively. Whereas inhibitor attachment had no effect on the plasminogen binding activity of FBA-tb, it competed with the natural substrate of the enzyme, fructose 1,6-bisphosphate, and substantiated a previously unknown reaction mechanism associated with metallodependent aldolases involving recruitment of the catalytic zinc ion by the substrate upon active site binding. Altogether, our results highlight the potential of FBA-tb as a novel therapeutic target against both replicating and non-replicating bacilli.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Biochemistry and Molecular Biology
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
FBA
dc.subject
DRUG TARGET
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PERSISTENCE
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MYCOBACTERIUM TUBERCULOSIS
dc.subject.classification
Biología Celular, Microbiología
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-04-14T15:47:35Z
dc.journal.volume
286
dc.journal.number
46
dc.journal.pagination
40219-40231
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Bethesda, Maryland
dc.description.fil
Fil: Santangelo, María de la Paz. State University of Colorado - Fort Collins; Estados Unidos. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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Fil: Gest, Petra M.. State University of Colorado - Fort Collins; Estados Unidos
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Fil: Guerin, Marcelo E.. Universidad del País Vasco; España
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Fil: Coinçon, Mathieu. University of Montreal; Canadá
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Fil: Pham, Ha. State University of Colorado - Fort Collins; Estados Unidos
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Fil: Ryan, Gavin. State University of Colorado - Fort Collins; Estados Unidos
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Fil: Puckett, Susan E.. Cornell University; Estados Unidos
dc.description.fil
Fil: Spencer, John S.. State University of Colorado - Fort Collins; Estados Unidos
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Fil: Gonzalez Juarrero, Mercedes. State University of Colorado - Fort Collins; Estados Unidos
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Fil: Daher, Racha. Universite de Paris XI. Institut de Chimie Moléculaire et des Matériaux d'Orsay; Francia
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Fil: Lenaerts, Anne J.. State University of Colorado - Fort Collins; Estados Unidos
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Fil: Schnappinger, Dirk. Cornell University; Estados Unidos
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Fil: Therisod, Michel. Universite de Paris XI. Institut de Chimie Moléculaire et des Matériaux d'Orsay; Francia
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Fil: Ehrt, Sabine. Cornell University; Estados Unidos
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Fil: Sygusch, Jurgen. University of Montreal; Canadá
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Fil: Jackson, Mary. State University of Colorado - Fort Collins; Estados Unidos
dc.journal.title
Journal of Biological Chemistry (online)
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S002192582050519X
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1074/jbc.M111.259440
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