RT Journal Article
T1 A New Pathway for Protein Haptenation by β‐Lactams
A1 Pérez Ruiz, Raúl
A1 Lence Quintana, Emilio José
A1 Andreu, Inmaculada
A1 Limones Herrero, Daniel
A1 González Bello, Concepción
A1 Miranda, Miguel A.
A1 Jiménez, Consuelo M.
K1 Allergy
K1 Lactams
K1 Molecular dynamics
K1 Photochemistry
K1 Proteins
AB 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)
PB Wiley
YR 2017
FD 2017-08-09
LK http://hdl.handle.net/10347/16940
UL http://hdl.handle.net/10347/16940
LA eng
NO 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
NO 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
NO Ministerio de Economía y Competitividad. Grant Numbers: CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2013-42899-R, SAF2016-75638-RGeneralitat Valenciana. Grant Number: PROMETEOII/2013/005Instituto de Salud Carlos III. Grant Numbers: RD12/0013/009, RD16/0006/0030Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Number: ED431G/09European Regional Development Fund
DS Minerva
RD 24 abr 2026