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State-of-the-Art Biochemistry in Spain

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 26552

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Special Issue Editors

Prof. Dr. Carlos Gutierrez-Merino

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Collection Editor

Professor of Biochemistry and Molecular Biology, Department of Biochemistry and Molecular Biology, Faculty of Sciences, and Institute of Molecular Pathology Biomarkers, University of Extremadura, Badajoz, Spain
Interests: tissue degeneration; biomaker; amyloid β-calmodulin
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. José Manuel González Ros

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Collection Editor

Instituto de Biología Molecular y Celular Universidad Miguel Hernández de Elche Edificio Torregaitán, Elche, Alicante, Spain
Interests: structure/function relationships in membrane proteins: neuroreceptors and ion channels; lipid–protein and protein–protein interactions in biological membranes; potential applications to drug discovery
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Dr. Jose Javier Lopez

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Collection Editor

Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Cáceres, Spain
Interests: physiology; pathophysiology; breast cancer; calcium homeostasis; store-operated calcium entry; STIM; orai; TRPC
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Regional Project aims to collect high-quality research articles, review articles, and communications on all aspects of biochemistry from Spain. We encourage the submission of manuscripts that provide novel and mechanistic insights and papers that report significant advances in the fields.

The areas of interest for the regional collection include but are not limited to topics such as:

Cellular function and structure;
Cell signaling;
Cell Metabolism;
Proteostasis and disease;
Protein biosynthesis;
Gene and protein structure and expression;
Cancer pathology and biology;
Aging biology and age-related diseases;
Drugs and pharmaceutics;
Post-translational modifications in health and disease;
New approaches in the management of hypoxic tumors;
Cancer metabolism and molecular genetics;
Enzymology and structural biology;
Metalloenzymes;
Enzyme activation and inhibition;
Targeting human enzymes involved in tumorigenesis;
Function and structure of lipid membrane;
Drug distribution and drug resistance;
Protein interactions and functional nucleic acids;
Epigenetic and genetic regulatory mechanisms;
Lipid metabolism;
Role of intestinal microbes in diseases and human health;
Characterization and development of small molecules for targeting metabolic pathways essential for the life cycle of human pathogens;
Neurochemistry;
Glycobiology;
Immunology;
Stem cell biology;
Regenerative therapy;
Membrane channels and transporters;
Membrane receptors;
Molecular Bioenergetics.

Prof. Dr. Carlos Gutierrez-Merino
Prof. Dr. José Manuel González Ros
Dr. Jose Javier Lopez
Collection Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (13 papers)

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19 pages, 2541 KiB

Open AccessArticle

Protein Susceptibility to Peroxidation by 4-Hydroxynonenal in Hereditary Hemochromatosis

by Sandra Sánchez-Jaut, Susana Pérez-Benavente, Paloma Abad, Darío Méndez-Cuadro, Antonio Puyet, Amalia Diez, Gonzalo Galicia-Poblet, Elena Gómez-Domínguez, María J. Moran-Jiménez, José M. Bautista and Isabel G. Azcárate

Int. J. Mol. Sci. 2023, 24(3), 2922; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032922 - 02 Feb 2023

Cited by 2 | Viewed by 1727

Abstract

Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe^−/− male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe^−/− mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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13 pages, 1181 KiB

Open AccessArticle

The D165H Polymorphism of QiMYB-like-1 Is Linked to Interactions between Tannin Accumulation, Herbivory and Biogeographical Determinants of Quercus ilex

by Alejandro Gallardo, David Morcuende, Manuela Rodríguez-Romero, María Isabel Igeño, Fernando Pulido and Alberto Quesada

Int. J. Mol. Sci. 2023, 24(1), 151; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010151 - 21 Dec 2022

Viewed by 930

Abstract

The accumulation in the leaves and young stems of phenolic compounds, such as hydrolyzable and condensed tannins, constitutes a defense mechanism of plants against herbivores. Among other stressing factors, chronic herbivory endangers Quercus ilex, a tree playing a central role in Mediterranean forests. This work addressed the connections between the chemical defenses of Q. ilex leaves and their susceptibility to herbivory, quantitative traits whose relationships are modulated by environmental and genetic factors that could be useful as molecular markers for the selection of plants with improved fitness. A search for natural variants detected the polymorphism D165H in the effector domain of QiMYB-like-1, a TT2-like transcription factor whose family includes members that control the late steps of condensed tannins biosynthesis in different plant species. QiMYB-like-1 D165H polymorphism was screened by PCR-RFLP in trees from six national parks in Spain where Q. ilex has a relevant presence, revealing that, unlike most regions that match the Hardy-Weinberg equilibrium, homozygous plants are over-represented in “Monfragüe” and “Cabañeros”, among the best examples to represent the continental Mediterranean (cM) ecosystem. Accordingly, the averages of two stress-related quantitative traits measured in leaves, herbivory index and accumulation of condensed tannins, showed asymmetric distributions depending on the clustering of trees based on ecological and genetic factors. Thus, the impact of herbivory was greater in managed forests with a low density of trees from the cM region, among which QiMYB-like-1 D165 homozygotes stand out, whereas condensed tannins accumulation was higher in leaves of QiMYB-like-1 H165 homozygotes from low-density forests, mainly in the Pyrenean (Py) region. Besides, the correlation between the contents of condensed tannins and total tannins vanished after clustering by the same factors: the cM region singularity, forest tree density, and QiMYB-like-1 genotype, among which homozygous shared the lowest link. The biogeographical and genetic constraints that modulate the contribution of condensed tannins to chemical defenses also mediated their interactions with the herbivory index, which was found positively correlated with total phenolics or tannins, suggesting an induction signal by this biotic stress. In contrast, a negative correlation was observed with condensed tannins after tree clustering by genetics factors where associations between tannins were lost. Therefore, condensed tannins might protect Q. ilex from defoliation in parks belonging to the cM ecosystem and carrying genetic factor(s) linked to the QiMYB-like-1 D165H polymorphism. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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16 pages, 3736 KiB

Open AccessArticle

Opposing Actions of TLR2 and TLR4 in Adipocyte Differentiation and Mature-Onset Obesity

by Natalia Cuesta, Sonia Fernández-Veledo, Carmen Punzón, Cristóbal Moreno, Beatriz Barrocal, Vinatha Sreeramkumar, Manuel Desco and Manuel Fresno

Int. J. Mol. Sci. 2022, 23(24), 15682; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415682 - 10 Dec 2022

Cited by 4 | Viewed by 1446

Abstract

Understanding the signaling cascades that govern adipocyte metabolism and differentiation is necessary for the development of therapies for obesity. Toll-like receptors (TLRs) are key mediators in adipogenesis, but their specific role is not completely understood. In this study, siRNA knockdown of Tlr2 in 3T3-L1 cells allowed them to differentiate more efficiently into adipocytes, whereas the opposite was observed for the knockdown of Tlr4. At the same time, we show that TLR2 knock-out mice spontaneously developed mature-onset obesity and insulin resistance. Besides a higher incidence of hyperplasia and hypertrophy in white adipose tissue (WAT), we found a significantly increased number of adipocyte precursor cells in TLR2^−/− mice compared to TLR4^−/− mice. Interestingly, genetic inactivation of Tlr4 in TLR2^−/− mice reverted their increased adiposity, insulin resistance, and restored normal levels of adipocyte precursor cells. These findings provide evidence that TLR2 and TLR4 play opposing roles in WAT homeostasis and point to the existence of cross-regulation among TLR2 and TLR4 during adipocyte differentiation both in vitro and in vivo. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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20 pages, 2749 KiB

Open AccessArticle

Deciphering the Role and Signaling Pathways of PKCα in Luminal A Breast Cancer Cells

by Emilio M. Serrano-López, Teresa Coronado-Parra, Consuelo Marín-Vicente, Zoltan Szallasi, Victoria Gómez-Abellán, María José López-Andreo, Marcos Gragera, Juan C. Gómez-Fernández, Rubén López-Nicolás and Senena Corbalán-García

Int. J. Mol. Sci. 2022, 23(22), 14023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214023 - 14 Nov 2022

Cited by 1 | Viewed by 1590

Abstract

Protein kinase C (PKC) comprises a family of highly related serine/threonine protein kinases involved in multiple signaling pathways, which control cell proliferation, survival, and differentiation. The role of PKCα in cancer has been studied for many years. However, it has been impossible to establish whether PKCα acts as an oncogene or a tumor suppressor. Here, we analyzed the importance of PKCα in cellular processes such as proliferation, migration, or apoptosis by inhibiting its gene expression in a luminal A breast cancer cell line (MCF-7). Differential expression analysis and phospho-kinase arrays of PKCα-KD vs. PKCα-WT MCF-7 cells identified an essential set of proteins and oncogenic kinases of the JAK/STAT and PI3K/AKT pathways that were down-regulated, whereas IGF1R, ERK1/2, and p53 were up-regulated. In addition, unexpected genes related to the interferon pathway appeared down-regulated, while PLC, ERBB4, or PDGFA displayed up-regulated. The integration of this information clearly showed us the usefulness of inhibiting a multifunctional kinase-like PKCα in the first step to control the tumor phenotype. Then allowing us to design a possible selection of specific inhibitors for the unexpected up-regulated pathways to further provide a second step of treatment to inhibit the proliferation and migration of MCF-7 cells. The results of this study suggest that PKCα plays an oncogenic role in this type of breast cancer model. In addition, it reveals the signaling mode of PKCα at both gene expression and kinase activation. In this way, a wide range of proteins can implement a new strategy to fine-tune the control of crucial functions in these cells and pave the way for designing targeted cancer therapies. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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18 pages, 3022 KiB

Open AccessArticle

Crosstalk between CXCR4/ACKR3 and EGFR Signaling in Breast Cancer Cells

by Maria Neves, Viviana Marolda, Federico Mayor, Jr. and Petronila Penela

Int. J. Mol. Sci. 2022, 23(19), 11887; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911887 - 06 Oct 2022

Cited by 1 | Viewed by 1718

Abstract

A better understanding of the complex crosstalk among key receptors and signaling pathways involved in cancer progression is needed to improve current therapies. We have investigated in cell models representative of the major subtypes of breast cancer (BC) the interplay between the chemokine CXCL12/CXCR4/ACKR3 and EGF receptor (EGFR) family signaling cascades. These cell lines display a high heterogeneity in expression profiles of CXCR4/ACKR3 chemokine receptors, with a predominant intracellular localization and different proportions of cell surface CXCR4+, ACKR3+ or double-positive cell subpopulations, and display an overall modest activation of oncogenic pathways in response to exogenous CXCL12 alone. Interestingly, we find that in MDA-MB-361 (luminal B subtype, Her2-overexpressing), but not in MCF7 (luminal A) or MDA-MB-231 (triple negative) cells, CXCR4/ACKR3 and EGFR receptor families share signaling components and crosstalk mechanisms to concurrently promote ERK1/2 activation, with a key involvement of the G protein-coupled receptor kinase 2 (GRK2) signaling hub and the cytosolic tyrosine kinase Src. Our findings suggest that in certain BC subtypes, a relevant cooperation between CXCR4/ACKR3 and growth factor receptors takes place to integrate concurrent signals emanating from the tumor microenvironment and foster cancer progression. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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18 pages, 2375 KiB

Open AccessArticle

HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells

by Roberto Beteta-Göbel, Marc Miralles, Javier Fernández-Díaz, Raquel Rodríguez-Lorca, Manuel Torres, Paula Fernández-García, Pablo V. Escribá and Victoria Lladó

Int. J. Mol. Sci. 2022, 23(17), 9902; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179902 - 31 Aug 2022

Viewed by 1972

Abstract

Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers. In this context, 2-hydroxycervonic acid (HCA) is a melitherapeutic agent developed to combat pancreatic cancer cells, provoking the programmed cell death by apoptosis of these cells by inducing ER stress and triggering the production of ROS species. The efficacy of HCA was demonstrated in vivo, alone and in combination with gemcitabine, using a MIA PaCa-2 cell xenograft model of pancreatic cancer in which no apparent toxicity was evident. HCA is metabolized by α-oxidation to C21:5n-3 (heneicosapentaenoic acid), which in turn also showed anti-proliferative effect in these cells. Given the unmet clinical needs associated with pancreatic cancer, the data presented here suggest that the use of HCA merits further study as a potential therapy for this condition. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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22 pages, 11904 KiB

Open AccessArticle

Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels

by Ana Marcela Giudici, María Lourdes Renart, Ana Coutinho, Andrés Morales, José Manuel González-Ros and José Antonio Poveda

Int. J. Mol. Sci. 2022, 23(16), 9246; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169246 - 17 Aug 2022

Cited by 1 | Viewed by 1216

Abstract

Y55W mutants of non-selective NaK and partly K⁺-selective NaK2K channels have been used to explore the conformational dynamics at the pore region of these channels as they interact with either Na⁺ or K⁺. A major conclusion is that these channels exhibit a remarkable pore conformational flexibility. Homo-FRET measurements reveal a large change in W55–W55 intersubunit distances, enabling the selectivity filter (SF) to admit different species, thus, favoring poor or no selectivity. Depending on the cation, these channels exhibit wide-open conformations of the SF in Na⁺, or tight induced-fit conformations in K⁺, most favored in the four binding sites containing NaK2K channels. Such conformational flexibility seems to arise from an altered pattern of restricting interactions between the SF and the protein scaffold behind it. Additionally, binding experiments provide clues to explain such poor selectivity. Compared to the K⁺-selective KcsA channel, these channels lack a high affinity K⁺ binding component and do not collapse in Na⁺. Thus, they cannot properly select K⁺ over competing cations, nor reject Na⁺ by collapsing, as K⁺-selective channels do. Finally, these channels do not show C-type inactivation, likely because their submillimolar K⁺ binding affinities prevent an efficient K⁺ loss from their SF, thus favoring permanently open channel states. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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14 pages, 12974 KiB

Open AccessArticle

Efficient Base-Catalyzed Kemp Elimination in an Engineered Ancestral Enzyme

by Luis I. Gutierrez-Rus, Miguel Alcalde, Valeria A. Risso and Jose M. Sanchez-Ruiz

Int. J. Mol. Sci. 2022, 23(16), 8934; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168934 - 11 Aug 2022

Cited by 5 | Viewed by 4228

Abstract

The routine generation of enzymes with completely new active sites is a major unsolved problem in protein engineering. Advances in this field have thus far been modest, perhaps due, at least in part, to the widespread use of modern natural proteins as scaffolds for de novo engineering. Most modern proteins are highly evolved and specialized and, consequently, difficult to repurpose for completely new functionalities. Conceivably, resurrected ancestral proteins with the biophysical properties that promote evolvability, such as high stability and conformational diversity, could provide better scaffolds for de novo enzyme generation. Kemp elimination, a non-natural reaction that provides a simple model of proton abstraction from carbon, has been extensively used as a benchmark in de novo enzyme engineering. Here, we present an engineered ancestral β-lactamase with a new active site that is capable of efficiently catalyzing Kemp elimination. The engineering of our Kemp eliminase involved minimalist design based on a single function-generating mutation, inclusion of an extra polypeptide segment at a position close to the de novo active site, and sharply focused, low-throughput library screening. Nevertheless, its catalytic parameters (k_cat/K_M~2·10⁵ M⁻¹ s⁻¹, k_cat~635 s⁻¹) compare favorably with the average modern natural enzyme and match the best proton-abstraction de novo Kemp eliminases that are reported in the literature. The general implications of our results for de novo enzyme engineering are discussed. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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21 pages, 8224 KiB

Open AccessArticle

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

by María Conde-Giménez, Juan José Galano-Frutos, María Galiana-Cameo, Alejandro Mahía, Bruno L. Victor, Sandra Salillas, Adrián Velázquez-Campoy, Rui M. M. Brito, José Antonio Gálvez, María D. Díaz-de-Villegas and Javier Sancho

Int. J. Mol. Sci. 2022, 23(9), 4502; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094502 - 19 Apr 2022

Cited by 1 | Viewed by 1891

Abstract

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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19 pages, 2718 KiB

Open AccessArticle

Erythrocyte Membrane Nanomechanical Rigidity Is Decreased in Obese Patients

by Jesús Sot, Aritz B. García-Arribas, Beatriz Abad, Sara Arranz, Kevin Portune, Fernando Andrade, Alicia Martín-Nieto, Olaia Velasco, Eunate Arana, Itziar Tueros, Carla Ferreri, Sonia Gaztambide, Félix M. Goñi, Luis Castaño and Alicia Alonso

Int. J. Mol. Sci. 2022, 23(3), 1920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031920 - 08 Feb 2022

Cited by 8 | Viewed by 2385

Abstract

This work intends to describe the physical properties of red blood cell (RBC) membranes in obese adults. The hypothesis driving this research is that obesity, in addition to increasing the amount of body fat, will also modify the lipid composition of membranes in cells other than adipocytes. Forty-nine control volunteers (16 male, 33 female, BMI 21.8 ± 5.6 and 21.5 ± 4.2 kg/m², respectively) and 52 obese subjects (16 male and 36 female, BMI 38.2± 11.0 and 40.7 ± 8.7 kg/m², respectively) were examined. The two physical techniques applied were atomic force microscopy (AFM) in the force spectroscopy mode, which allows the micromechanical measurement of penetration forces, and fluorescence anisotropy of trimethylammonium diphenylhexatriene (TMA-DPH), which provides information on lipid order at the membrane polar–nonpolar interface. These techniques, in combination with lipidomic studies, revealed a decreased rigidity in the interfacial region of the RBC membranes of obese as compared to control patients, related to parallel changes in lipid composition. Lipidomic data show an increase in the cholesterol/phospholipid mole ratio and a decrease in sphingomyelin contents in obese membranes. ω-3 fatty acids (e.g., docosahexaenoic acid) appear to be less prevalent in obese patient RBCs, and this is the case for both the global fatty acid distribution and for the individual major lipids in the membrane phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS). Moreover, some ω-6 fatty acids (e.g., arachidonic acid) are increased in obese patient RBCs. The switch from ω-3 to ω-6 lipids in obese subjects could be a major factor explaining the higher interfacial fluidity in obese patient RBC membranes. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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Review

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20 pages, 3892 KiB

Open AccessReview

Progress in the Structural Basis of thermoTRP Channel Polymodal Gating

by Gregorio Fernández-Ballester, Asia Fernández-Carvajal and Antonio Ferrer-Montiel

Int. J. Mol. Sci. 2023, 24(1), 743; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010743 - 01 Jan 2023

Cited by 6 | Viewed by 1918

Abstract

The thermosensory transient receptor potential (thermoTRP) family of ion channels is constituted by several nonselective cation channels that are activated by physical and chemical stimuli functioning as paradigmatic polymodal receptors. Gating of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Given that thermoTRP channels integrate diverse physical and chemical stimuli, a thorough understanding of the molecular mechanisms underlying polymodal gating has been pursued, including the interplay between stimuli and differences between family members. Despite its complexity, recent advances in cryo-electron microscopy techniques are facilitating this endeavor by providing high-resolution structures of these channels in different conformational states induced by ligand binding or temperature that, along with structure-function and molecular dynamics, are starting to shed light on the underlying allosteric gating mechanisms. Because dysfunctional thermoTRP channels play a pivotal role in human diseases such as chronic pain, unveiling the intricacies of allosteric channel gating should facilitate the development of novel drug-based resolving therapies for these disorders. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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20 pages, 1712 KiB

Open AccessReview

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

by Claudia M. Rejano-Gordillo, Beatriz Marín-Díaz, Ana Ordiales-Talavero, Jaime M. Merino, Francisco J. González-Rico and Pedro M. Fernández-Salguero

Int. J. Mol. Sci. 2022, 23(23), 14919; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314919 - 29 Nov 2022

Cited by 6 | Viewed by 1906

Abstract

The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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14 pages, 1328 KiB

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Sea Anemones, Actinoporins, and Cholesterol

by Juan Palacios-Ortega, Diego Heras-Márquez, Rafael Amigot-Sánchez, Carmen García-Montoya, Carlos Torrijos, Diego Laxalde, José G. Gavilanes, Sara García-Linares and Álvaro Martínez-del-Pozo

Int. J. Mol. Sci. 2022, 23(15), 8771; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158771 - 07 Aug 2022

Cited by 1 | Viewed by 2046

Abstract

Spanish or Spanish-speaking scientists represent a remarkably populated group within the scientific community studying pore-forming proteins. Some of these scientists, ourselves included, focus on the study of actinoporins, a fascinating group of metamorphic pore-forming proteins produced within the venom of several sea anemones. These toxic proteins can spontaneously transit from a water-soluble fold to an integral membrane ensemble because they specifically recognize sphingomyelin in the membrane. Once they bind to the bilayer, they subsequently oligomerize into a pore that triggers cell-death by osmotic shock. In addition to sphingomyelin, some actinoporins are especially sensible to some other membrane components such as cholesterol. Our group from Universidad Complutense of Madrid has focused greatly on the role played by sterols in this water–membrane transition, a question which still remains only partially solved and constitutes the main core of the article below. Full article

(This article belongs to the Special Issue State-of-the-Art Biochemistry in Spain)

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