Journal Article Research Support, Non-U.S. Gov't Ppublish 5 citations
PubMed: 37311331 DOI: 10.1016/j.jmgm.2023.108533
Cysteine carbonylation with reactive carbonyl species from lipid peroxidation induce local structural changes on thioredoxin active site.
J Mol Graph Model 124:108533
Authors: Rafael Pineda-Alemán, Antistio Alviz-Amador, Rodrigo Galindo-Murillo, Humberto Pérez-González, Erika Rodríguez-Cavallo, Darío Méndez-Cuadro
Affiliations
- Analytical Chemistry and Biomedicine Group, Medicine Faculty, University of Cartagena, Cartagena, Colombia.
- Analytical Chemistry and Biomedicine Group, Pharmaceutical Sciences Faculty, University of Cartagena, Cartagena, Colombia.
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA.
- Department of Mathematics, Exact and Natural Sciences Faculty, University of Cartagena, Cartagena, Colombia.
- Analytical Chemistry and Biomedicine Group, Pharmaceutical Sciences Faculty, University of Cartagena, Cartagena, Colombia.
- Analytical Chemistry and Biomedicine Group, Exact and Natural Sciences Faculty, University of Cartagena, Colombia.
Abstract
Protein oxidative modifications with reactive carbonyl species (RCS) is directly linked to metabolic processes in premature aging, cancer, neurodegenerative and infectious diseases. RCS as 4-Hydroxy-2-nonal (HNE), 4-Hydroxy-2-hexenal (HHE), 4-Oxo-2-nonenal (ONE) and Malondialdehyde (MDA) attack nucleophilic amino acids residues forming irreversible adducts with proteins as Thioredoxins (Trx). This is a class of small thiol oxide-reductases playing a key role in redox signaling and oxidative stress responses in mammals. Although proteomic studies have identified to Cys-32 residue as a target of HNE attack that inhibit its enzymatic activity, how this carbonylation affects its structure and dynamic behavior at the atomic level is unknown. Even more, the molecular bases for the atomistic behavior of these modified proteins have not been completely understood. We present molecular dynamics simulations of Trx-modified with four different RCS to analyze its global and local structural effects. For this, parameters supported in the AMBER force fields were built and validated for three non-natural cysteine residues modified with HHE, ONE and MDA. Results obtained showed a slight change in the global conformational stability of Trx modified with HNE and MDA, establishing that all modified proteins presented local regions of high mobility in the modified catalytic site and some regions far from the modification area. In addition, essential domain movement modes evidences that proteins modified with the RCS assayed induce changes in conformational flexibility. Finally, these data showed that the given conformational changes did not caused global changes in proteins but rather localized changes in particular regions.
MeSH
Cysteine, Thioredoxins