Adrián Velazquez‐Campoy

Universidad de Zaragoza

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Olga Abián

Universidad de Zaragoza

113

Sonia Vega

Universidad de Zaragoza

José L. Neira

Universitat de Miguel Hernández d'Elx

Javier Sancho

Universidad de Zaragoza

Bruno Rizzuti

University of Calabria

ÁL

Ángel Lanas

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Ernesto Freire

Johns Hopkins University

Milagros Medina

Universidad de Zaragoza

Rafael Claveria‐Gimeno

Universidad de Zaragoza

David Ortega-Alarcón

Universidad de Zaragoza

Cooperative Institutions

Universidad de Zaragoza

183

Consejo Superior de Investigaciones Científicas

179

Centre National de la Recherche Scientifique

Instituto de Investigación Sanitaria Aragón

Universidad de Sevilla

Universidad Autónoma de Madrid

Inserm

Instituto de Biocomputación y Física de Sistemas Complejos

Universitat Autònoma de Barcelona

Centro de Investigación Biomédica en Red

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In Vitro Antiviral Activity of Tyrosinase from Mushroom Agaricus bisporus against Hepatitis C Virus

Pharmaceuticals (2021)

David Lopez‐Tejedor Rafael Claveria‐Gimeno Adrián Velazquez‐Campoy Olga Abián José M. Palomo

Tyrosinases from a commercial Agaricus bisporus protein extract and directly isolated from white mushrooms were purified in order to obtaining the well-known tyrosinase from A. bisporus (TyrAB) of 45 kDa and a newly discovered 50 kDa tyrosinase isoform (Tyr50 kDa), and tested showing high antiviral activity against the hepatitis C virus for the first time. Cell toxicity and antiviral activity of tyrosinases were determined in cultured Huh 5-2 liver tumor cells transfected with a replicon system (a plasmid that includes all non-structural hepatitis C virus proteins and replicates autonomously). TyrAB was able to inhibit the replication of the hepatitis C virus without inducing toxicity in liver cells. In addition, the post-translational isoform Tyr50 kDa showed higher antiviral capacity than the former (up to 10 times greater), also exhibiting 10 times higher activity than the commercial drug Ribavirin®. This antiviral activity was directly proportional to the enzymatic activity of tyrosinases, as no antiviral capacity was observed in the inactive form of the enzymes. The tyrosinases approach could represent a new antiviral inhibition mechanism, through a plausible catalytic mechanism of selective hydroxylation of the key role of tyrosine residues in viral proteases.

Agaricus bisporus

Antiviral protein

10.3390/ph14080759

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Citations (9)

CCDC 1979343: Experimental Crystal Structure Determination

The Cambridge Structural Database (2021)

Lucı́a González Sara Graus Blanca Gaspar Sheila Espasa Adrián Velazquez‐Campoy

10.5517/ccdc.csd.cc24fns1

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Novel Drug-like HsrA Inhibitors Exhibit Potent Narrow-Spectrum Antimicrobial Activities against <em>Helicobacter pylori</em>

Javier Casado Irene Olivan‐Muro Sonia Algarate Eduardo Chueca Sandra Salillas

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase of multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide, encouraging scientific community to discover and develop new antimicrobial strategies. In the present work, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against antibiotic-resistant strains of H. pylori. Most of these novel antimicrobials exhibited minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, additive effect in combination with metronidazole and clarithromycin, as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggested that in vivo inhibition of HsrA triggered lethal global disturbances in H. pylori physiology, including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori.

Antimicrobial drug

10.20944/preprints202409.0421.v1

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Evolutionarily conserved proteins MnmE and GidA catalyze the formation of two methyluridine derivatives at tRNA wobble positions

Nucleic Acids Research (2009)

Ismaïl Moukadiri Silvia Díaz‐Prado Julio Piera Adrián Velazquez‐Campoy Glenn R. Björk

The wobble uridine of certain bacterial and mitochondrial tRNAs is modified, at position 5, through an unknown reaction pathway that utilizes the evolutionarily conserved MnmE and GidA proteins. The resulting modification (a methyluridine derivative) plays a critical role in decoding NNG/A codons and reading frame maintenance during mRNA translation. The lack of this tRNA modification produces a pleiotropic phenotype in bacteria and has been associated with mitochondrial encephalomyopathies in humans. In this work, we use in vitro and in vivo approaches to characterize the enzymatic pathway controlled by the Escherichia coli MnmE•GidA complex. Surprisingly, this complex catalyzes two different GTP- and FAD-dependent reactions, which produce 5-aminomethyluridine and 5-carboxymethylamino-methyluridine using ammonium and glycine, respectively, as substrates. In both reactions, methylene-tetrahydrofolate is the most probable source to form the C5-methylene moiety, whereas NADH is dispensable in vitro unless FAD levels are limiting. Our results allow us to reformulate the bacterial MnmE•GidA dependent pathway and propose a novel mechanism for the modification reactions performed by the MnmE and GidA family proteins.

Wobble base pair

10.1093/nar/gkp762

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Citations (105)

Direct examination of the relevance for folding, binding and electron transfer of a conserved protein folding intermediate

Physical Chemistry Chemical Physics (2017)

Emilio Lamazares Sonia Vega Patrícia Ferreira Milagros Medina Juan José Galano‐Frutos

Protein engineering allows testing the role of conserved folding intermediates at the native basins of proteins.

Folding (DSP implementation)

Relevance

10.1039/c7cp02606d

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Citations (4)

Characterisation of ligand binding by calorimetry

Ernesto Freire Yuko Kawasaki Adrián Velazquez‐Campoy Arne Schön

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Citations (3)

Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases

Nature Communications (2015)

Rubén M. Buey Rodrigo Ledesma‐Amaro Adrián Velazquez‐Campoy Mónica Balsera Mónica Chagoyen

Abstract Inosine-5′-monophosphate dehydrogenase (IMPDH) plays key roles in purine nucleotide metabolism and cell proliferation. Although IMPDH is a widely studied therapeutic target, there is limited information about its physiological regulation. Using Ashbya gossypii as a model, we describe the molecular mechanism and the structural basis for the allosteric regulation of IMPDH by guanine nucleotides. We report that GTP and GDP bind to the regulatory Bateman domain, inducing octamers with compromised catalytic activity. Our data suggest that eukaryotic and prokaryotic IMPDHs might have developed different regulatory mechanisms, with GTP/GDP inhibiting only eukaryotic IMPDHs. Interestingly, mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, our results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies, opening the door to new therapeutic approaches.

10.1038/ncomms9923

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Citations (75)

Antimalarial Activity of Cupredoxins

Journal of Biological Chemistry (2013)

Isabel Cruz‐Gallardo Irene Dίaz–Moreno Antonio Díaz‐Quintana Antonio Donaire Adrián Velazquez‐Campoy

The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design.

Isothermal Titration Calorimetry

10.1074/jbc.m113.460162

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Citations (9)

Development of a Machine‐Learning Model for Diagnosis of Pancreatic Cancer from Serum Samples Analyzed by Thermal Liquid Biopsy

Advanced Intelligent Systems (2024)

Sonia Hermoso‐Durán Nicolás A. Fraunhoffer Judith Millastre‐Bocos Oscar Sanchez‐Gracia Pablo F. Garrido

Pancreatic ductal adenocarcinoma (PDAC) poses a considerable diagnostic and therapeutic challenge due to the lack of specific biomarkers and late diagnosis. Early detection is crucial for improving prognosis, but current techniques are insufficient. An innovative approach based on differential scanning calorimetry (DSC) of blood serum samples, thermal liquid biopsy (TLB), combined with machine‐learning (ML) analysis, may offer a more efficient method for diagnosing PDAC. Serum samples from a cohort of 212 PDAC patients and 184 healthy controls are studied. DSC thermograms are analyzed using ML models. The generated models are built applying algorithms based on penalized regression, resampling, categorization, cross validation, and variable selection. The ML‐based model demonstrates outstanding ability to discriminate between PDAC patients and control subjects, with a sensitivity of 90% and an area under the ROC receiver operating characteristic curve of 0.83 in the training and test groups. Application of the model to an independent validation cohort of 113 PDAC patients confirms its robustness and utility as a diagnosis tool. The application of ML to serum TLB data emerges as a promising methodology for early diagnosis, representing a significant advance for detecting and managing PDAC, envisaging a minimally invasive and more efficient methodology for identifying biomarkers.

Liquid biopsy

10.1002/aisy.202400308

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Citations (1)

Citrullinating enzyme PADI4 and transcriptional repressor RING1B bind in cancer cells

International Journal of Biological Macromolecules (2024)

Salomé Araujo‐Abad Bruno Rizzuti Lourdes Soto-Conde Miguel Vidal Olga Abián

Polycomb groups (PcGs) are transcriptional repressors, formed by a complex of several proteins, involved in multicellular development and cancer epigenetics. One of these proteins is the E3 ubiquitin-protein ligase RING1 (or RING1B), associated with the regulation of transcriptional repression and responsible for monoubiquitylation of the histone H2A. On the other hand, PADI4 is one of the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline, and it is also involved in the development of glioblastoma, among other types of cancers. In this work, we showed the association of PADI4 and RING1B in the nucleus and cytosol in several cancer cell lines by using immunofluorescence and proximity ligation assays. Furthermore, we demonstrated that binding was hampered in the presence of GSK484, an enzymatic PADI4 inhibitor, suggesting that RING1B could bind to the active site of PADI4, as confirmed by protein-protein docking simulations. In vitro and in silico findings showed that binding to PADI4 occurred for the isolated fragments corresponding to both the N-terminal (residues 1–221) and C-terminal (residues 228–336) regions of RING1B. Binding to PADI4 was also hampered by GSK484, as shown by isothermal titration calorimetry (ITC) experiments for the sole N-terminal region, and by both NMR and ITC for the C-terminal one. The dissociation constants between PADI4 and any of the two isolated RING1B fragments were in the low micromolar range (~2–10 μM), as measured by fluorescence and ITC. The interaction between RING1B and PADI4 might imply citrullination of the former, leading to several biological consequences, as well as being of potential therapeutic relevance for improving cancer treatment with the generation of new antigens.

10.1016/j.ijbiomac.2024.133163

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Citations (1)