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http://hdl.handle.net/10261/205089
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dc.contributor.author | Castellví, Albert | - |
dc.contributor.author | Crespo, Isidro | - |
dc.contributor.author | Crosas, Eva | - |
dc.contributor.author | Cámara-Artigas, Ana | - |
dc.contributor.author | Gavira Gallardo, J. A. | - |
dc.contributor.author | Aranda, M. A. G. | - |
dc.contributor.author | Parés, Xavier | - |
dc.contributor.author | Juanhuix, Judith | - |
dc.date.accessioned | 2020-03-25T10:29:14Z | - |
dc.date.available | 2020-03-25T10:29:14Z | - |
dc.date.issued | 2019-02-28 | - |
dc.identifier | doi: 10.1038/s41598-019-39722-0 | - |
dc.identifier | issn: 2045-2322 | - |
dc.identifier.citation | Scientific Reports 9: 3117 (2019) | - |
dc.identifier.uri | http://hdl.handle.net/10261/205089 | - |
dc.description.abstract | Human aldose reductase (hAR, AKR1B1) has been explored as drug target since the 1980s for its implication in diabetic complications. An activated form of hAR was found in cells from diabetic patients, showing a reduced sensitivity to inhibitors in clinical trials, which may prevent its pharmacological use. Here we report the conversion of native hAR to its activated form by X-ray irradiation simulating oxidative stress conditions. Upon irradiation, the enzyme activity increases moderately and the potency of several hAR inhibitors decay before global protein radiation damage appears. The catalytic behavior of activated hAR is also reproduced as the KM increases dramatically while the kcat is not much affected. Consistently, the catalytic tetrad is not showing any modification. The only catalytically-relevant structural difference observed is the conversion of residue Cys298 to serine and alanine. A mechanism involving electron capture is suggested for the hAR activation. We propose that hAR inhibitors should not be designed against the native protein but against the activated form as obtained from X-ray irradiation. Furthermore, since the reactive species produced under irradiation conditions are the same as those produced under oxidative stress, the described irradiation method can be applied to other relevant proteins under oxidative stress environments | - |
dc.description.sponsorship | This work was started, and partly supported by a grant from the Spanish Nuclear Council (CSN). We are indebted to Alexandra Cousido-Siah and Alberto Podjarny (IGBMC-CNRS-Univ. Strasbourg) for the expression plasmid and seeds. The authors thank the teams of beamlines BL13-XALOC at ALBA Synchrotron and B21 at Diamond for their support during the MX and SAXS experiments, respectively, and the BioStruct-X grant (agreement N°283570) under the EC 7th Framework Programme (FP7/2007–2013) for the access to the B21 beamline. We also thank the technical services of Dr. Eliandre de Oliveira and María Antonia Odena at the Plataforma de Proteòmica of the University of Barcelona for the LC-MS/MS measurements and suggestions. | - |
dc.language | eng | - |
dc.publisher | Nature Publishing Group | - |
dc.relation | info:eu-repo/grantAgreement/EC/FP7/283570 | - |
dc.relation.isversionof | Publisher's version | - |
dc.rights | openAccess | - |
dc.title | Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1038/s41598-019-39722-0 | - |
dc.relation.publisherversion | http://dx.doi.org/10.1038/s41598-019-39722-0 | - |
dc.date.updated | 2020-03-25T10:29:14Z | - |
dc.rights.license | https://creativecommons.org/licenses/by/4.0/ | - |
dc.contributor.funder | Consejo de Seguridad Nuclear (España) | - |
dc.contributor.funder | European Commission | - |
dc.relation.csic | Sí | - |
dc.identifier.funder | http://dx.doi.org/10.13039/501100000780 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100006055 | es_ES |
dc.identifier.pmid | 30816220 | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.grantfulltext | open | - |
item.openairetype | artículo | - |
item.fulltext | With Fulltext | - |
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Scientific Report 9 3117.pdf | 3 MB | Adobe PDF | Visualizar/Abrir |
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