A New Pathway for Protein Haptenation by β‐Lactams
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Title: | A New Pathway for Protein Haptenation by β‐Lactams |
Author: | Pérez Ruiz, Raúl Lence Quintana, Emilio José Andreu, Inmaculada Limones Herrero, Daniel González Bello, Concepción Miranda, Miguel A. Jiménez, Consuelo M. |
Affiliation: | Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares Universidade de Santiago de Compostela. Departamento de Química Orgánica |
Subject: | Allergy | Lactams | Molecular dynamics | Photochemistry | Proteins | |
Date of Issue: | 2017-08-09 |
Publisher: | Wiley |
Citation: | Pérez-Ruíz, R., Lence, E., Andreu, I., Limones-Herrero, D., González-Bello, C., Miranda, M., & Jiménez, M. (2017). A New Pathway for Protein Haptenation by β-Lactams. Chemistry - A European Journal, 23(56), 13986-13994. doi: 10.1002/chem.201702643 |
Abstract: | The covalent binding of β‐lactams to proteins upon photochemical activation has been demonstrated by using an integrated approach that combines photochemical, proteomic and computational studies, selecting human serum albumin (HSA) as a target protein and ezetimibe (1) as a probe. The results have revealed a novel protein haptenation pathway for this family of drugs that is an alternative to the known nucleophilic ring opening of β‐lactams by the free amino group of lysine residues. Thus, photochemical ring splitting of the β‐lactam ring, following a formal retro‐Staudinger reaction, gives a highly reactive ketene intermediate that is trapped by the neighbouring lysine residues, leading to an amide adduct. For the investigated 1/HSA system, covalent modification of residues Lys414 and Lys525, which are located in sub‐domains IIIA and IIIB, respectively, occurs. The observed photobinding may constitute the key step in the sequence of events leading to photoallergy. Docking and molecular dynamics simulation studies provide an insight into the molecular basis of the selectivity of 1 for these HSA sub‐domains and the covalent modification mechanism. Computational studies also reveal positive cooperative binding of sub‐domain IIIB that explains the experimentally observed modification of Lys414, which is located in a barely accessible pocket (sub‐domain IIIA) |
Description: | This is the peer-reviewed version of the following article: Pérez-Ruíz, R., Lence, E., Andreu, I., Limones-Herrero, D., González-Bello, C., Miranda, M., & Jiménez, M. (2017). A New Pathway for Protein Haptenation by β-Lactams. Chemistry - A European Journal, 23(56), 13986-13994, which has been published in final form at https://doi.org/10.1002/chem.201702643. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-Archiving |
Publisher version: | https://doi.org/10.1002/chem.201702643 |
URI: | http://hdl.handle.net/10347/16940 |
DOI: | 10.1002/chem.201702643 |
E-ISSN: | 1521-3765 |
Rights: | © 2017 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-Archiving |
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