Artículos (Instituto de Investigaciones Químicas (IIQ) – CIC Cartuja)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10959

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Atroposelective Transfer Hydrogenation of Biaryl Aminals via Dynamic Kinetic Resolution. Synthesis of Axially Chiral Diamines
(American Chemical Society, 2021-03-18) Carmona, José A.; Rodríguez Franco, Carlos; López Serrano, Joaquín; Ros Lao, Abel; Iglesias Sigüenza, Francisco Javier; Fernández Fernández, Rosario; Lassaletta, José M.; Hornillos, Valentín; Universidad de Sevilla. Departamento de Química Inorgánica; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
An efficient dynamic kinetic resolution (DKR) approach for the synthesis of axially chiral diamines has been developed on the basis of a ruthenium-catalyzed enantioselective transfer hydrogenation. The strategy relies on the configurational instability of cyclic biaryl aminal precursors in equilibrium with their amino-imine open forms, as supported by DFT calculations. This protocol features a broad substrate scope of aliphatic amines and biaryl scaffolds and proceeds under very mild conditions, allowing the preparation of BINAM homologues in good to high yields and nearly perfect enantioselectivities (up to 99% ee).
A combined experimental and computational study to decipher complexity in the asymmetric hydrogenation of imines with Ru catalysts bearing atropisomerizable ligands
(Royal Society of Chemistry, 2021-01-21) León García, Félix; Comas-Vives, Aleix; Álvarez González, Eleuterio; Pizzano, Antonio; Universidad de Sevilla. Departamento de Química Inorgánica; Ministerio de Ciencia e Innovación (MICIN). España
RuCl2(P-OP)(N-N) complexes (1) containing an atropisomerizable phosphine-phosphite (P-OP) and a chiralC2symmetric diamine (N-N) are readily prepared astransisomers by successive addition of P-OP and N-N ligands to RuCl2(PPh3)3. For these complexes, fast atropisomerization of the biaryl fragment at room temperature has been observed. Compoundtrans-1acleanly isomerizes into a mixture ofcisisomers in EtOH upon heating. DFT calculations reproduce accurately the ratio of isomers observed as well as the greater thermodynamic stability of thecisisomers of1a. Complexes1are efficient catalyst precursors for the asymmetric hydrogenation ofN-aryl imines5in toluene under very mild conditions using KOtBu as a base (4 bar H2, room temperature,5/1/KOtBu = 500/1/10). Among the catalyst precursors,1fprovides good enantioselectivities in the hydrogenation of a wide range ofN-aryl imines (84-96% ee, 16 examples). From DFT calculations, a mechanism consisting in stepwise transfer of a hydride and a proton from the dihydride to the imine has been proposed, with the most favourable paths forRandSproducts involvingcis-dihydridesd1Randd3S, respectively. Among several hydrogen activation pathways examined in thepro-Rroute, the most favorable one consists of hydrogen coordination to a Ru-amido/amine adduct, followed by amine assisted activation of dihydrogen.
Full Potential of Microwave-assisted Processes: From Synthesis of High-quality MIL-101(Fe) Catalyst to Furfural Valorization
(Elsevier, 2024) Franco, Ana; Rodríguez Gómez, Salvador; Hamad, Said; Carrillo Carrión, Carolina; Universidad de Sevilla. Departamento de Química orgánica; Gobierno de España; Ministerio de Ciencia e Innovación (MICIN). España
Metal-organic frameworks (MOFs) have emerged as promising catalysts in biomass valorization processes, due to mainly their high structural and chemical flexibility when compared to other catalytic materials. However, it is still challenging to achieve perfect control in the synthetic method to obtain high-quality MOF particles containing uniform active sites, which will strongly influence their further catalytic performance. Herein, we have demonstrated that microwaves (MWs) can play a key role not only in the preparation of the MOF catalyst, specifically MIL-101(Fe), but also in performing the MOF-catalyzed oxidative esterification of furfural to methyl-2-furoate under mild conditions and in the absence of a base. MIL-101(Fe) exhibited a high conversion of furfural (>90 %) and excellent selectivity to methyl-2-furoate (>95 %) in just 1 h of reaction and at a moderate temperature (60 °C). A series of control experiments and DFT-mechanistic studies revealed the pivotal role played by the MIL-101(Fe) particles to drive the preferential formation of the target compound methyl-2-furoate, and evidenced that the MOF behaves as a truly heterogeneous catalyst. Overall, this work demonstrates that the potential of MW energy is underexploited, and highlights that there is still a long way to go in the development of new MOF-based catalytic approaches for biomass transformations.
Phosphorylation of cytochrome c at tyrosine 48 finely regulates its binding to the histone chaperone SET/TAF-Iβ in the nucleus
(Wiley, 2024-11-16) Tamargo Azpilicueta, Joaquín; Casado Combreras, Miguel Ángel; Giner Arroyo, Rafael Luis; Velázquez Campoy, Adrián; Márquez Escudero, Inmaculada; Olloqui Sariego, José Luis; Rosa Acosta, Miguel Ángel de la; Díaz Moreno, Irene; Universidad de Sevilla. Departamento de Química Física; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; European Union (UE); Junta de Andalucía
Post-translational modifications (PTMs) of proteins are ubiquitous processes present in all life kingdoms, involved in the regulation of protein stability, subcellular location and activity. In this context, cytochrome c (Cc) is an excellent case study to analyze the structural and functional changes induced by PTMS as Cc is a small, moonlighting protein playing different roles in different cell compartments at different cell-cycle stages. Cc is actually a key component of the mitochondrial electron transport chain (ETC) under homeostatic conditions but is translocated to the cytoplasm and even the nucleus under apoptotic conditions and/or DNA damage. Phosphorylation does specifically alter the Cc redox activity in the mitochondria and the Cc non-redox interaction with apoptosis-related targets in the cytoplasm. However, little is known on how phosphorylation alters the interaction of Cc with histone chaperones in the nucleus. Here, we report the effect of Cc Tyr48 phosphorylation by examining the protein interaction with SET/TAF-Iβ in the nuclear compartment using a combination of molecular dynamics simulations, biophysical and structural approaches such as isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) and in cell proximity ligation assays. From these experiments, we infer that Tyr48 phosphorylation allows a fine-tuning of the Cc-mediated inhibition of SET/TAF-Iβ histone chaperone activity in vitro. Our findings likewise reveal that phosphorylation impacts the nuclear, stress-responsive functions of Cc, and provide an experimental framework to explore novel aspects of Cc post-translational regulation in the nucleus.
Electrophilic Hydrosilylation of Electron-Rich Alkenes Derived from Enamines
(John Wiley & Sons, 2024-04-18) Laglera Gándara, Carlos J.; Fernández de Córdova, Francisco José; Jiménez Pérez, Julián; Ríos Moreno, Pablo; Conejero Iglesias, Salvador; Universidad de Sevilla. Departamento de Química Inorgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Universidad de Oviedo
The low-electron count, air-stable, platinum complexes [Pt(ItBu’)(ItBu)][BArF] (C1) (ItBu=1,3-di-tert-butylimidazol-2-ylidene), [Pt(SiPh)3(ItBuiPr)2][BArF] (C2) (ItBuiPr=1-tert-butyl-3-iso-propylimidazol-2-ylidene), [Pt(SiPh)3(ItBuMe)2][BArF] (C3), [Pt(GePh3)(ItBuiPr)2][BArF] (C4), [Pt(GePh)3(ItBuMe)2][BArF] (C5) and [Pt(GeEt)3(ItBuMe)2][BArF] (C6) (ItBuMe=1-tert-butyl-3-methylimidazol-2-ylidene) are efficient catalysts (particularly the germyl derivatives) in both the silylative dehydrocoupling and hydrosilylation of electron rich alkenes derived from enamines. The steric hindrance exerted by the NHC ligand plays an important role in the selectivity of the reaction. Thus, bulky ligands are selective towards the silylative dehydrocoupling process whereas less sterically hindered promote the selective hydrosilylation reaction. The latter is, in addition, regioselective towards the β-carbon atom of both internal and terminal enamines, leading to β-aminosilanes. Moreover, the syn stereochemistry of the amino and silyl groups implies an anti Si−H bond addition across the double bond. All these facts point to a mechanistic picture that, according to experimental and computational studies, involves a non-classical hydrosilylation process through an outer-sphere mechanism in which a formal nucleophilic addition of the enamine to the silicon atom of a platinum σ-SiH complex is the key step. This is in sharp contrast with the classical Chalk–Harrod mechanism prevalent in platinum chemistry.
Diborane Reductions of CO2 and CS2 Mediated by Dicopper μ-Boryl Complexes of a Robust Bis(phosphino)-1,8-naphthyridine Ligand
(American Chemical Society, 2024-05-03) See, Matthew S.; Ríos Moreno, Pablo; Tilley, T. Don; Universidad de Sevilla. Departamento de Química Inorgánica; Department of Energy. United States
A dinucleating 1,8-naphthyridine ligand featuring fluorene-9,9-diyl-linked phosphino side arms (PNNPFlu) was synthesized and used to obtain the cationic dicopper complexes 2, [(PNNPFlu)Cu2(μ-Ph)][NTf2]; [NTf2] = bis(trifluoromethane)sulfonimide, 6, [(PNNPFlu)Cu2(μ-CCPh)][NTf2], and 3, [(PNNPFlu)Cu2(μ-OtBu)][NTf2]. Complex 3 reacted with diboranes to afford dicopper μ-boryl species (4, with μ-Bcat; cat = catecholate and 5, with μ-Bpin; pin = pinacolate) that are more reactive in C(sp)-H bond activations and toward activations of CO2 and CS2, compared to dicopper μ-boryl complexes supported by a 1,8-naphthyridine-based ligand with di(pyridyl) side arms. The solid-state structures and DFT analysis indicate that the higher reactivities of 4 and 5 relate to changes in the coordination sphere of copper, rather than to perturbations on the Cu-B bonding interactions. Addition of xylyl isocyanide (CNXyl) to 4 gave 7, [(PNNPFlu)Cu2(μ-Bcat)(CNXyl)][NTf2], demonstrating that the lower coordination number at copper is chemically significant. Reactions of 4 and 5 with CO2 yielded the corresponding dicopper borate complexes (8, [(PNNPFlu)Cu2(μ-OBcat)][NTf2]; 9, [(PNNPFlu)Cu2(μ-OBpin)][NTf2]), with 4 demonstrating catalytic reduction in the presence of excess diborane. Related reactions of 4 and 5 with CS2 provided insertion products 10, {[(PNNPFlu)Cu2]2[μ-S2C(Bcat)2]}[NTf2]2, and 11, [(PNNPFlu)Cu2(μ,κ2-S2CBpin)][NTf2], respectively. These products feature Cu-S-C-B linkages analogous to those of proposed CO2 insertion intermediate.
Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis
(MDPI, 2022) Clemente, Francesca; Martínez Bailén, Macarena; Matassini, Camilla; Morrone, Amelia; Falliano, Silvia; Caciotti, Anna; Paoli, Paolo; Goti, Andrea; Cardona, Francesca; Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica
GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.
GCase Enhancers: A Potential Therapeutic Option for Gaucher Disease and Other Neurological Disorders
(MDPI, 2022) Martínez Bailén, Macarena; Clemente, Francesca; Matassini, Camilla; Cardona, Francesca; Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica
Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in misfolded lysosomal enzymes, can strongly benefit from the use of PCs able to facilitate their translocation to the lysosomes. This results in a recovery of their catalytic activity. No PC for the GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached the market yet, despite the importance of this enzyme not only for Gaucher disease, the most common LSD, but also for neurological disorders, such as Parkinson’s disease. This review aims to describe the efforts made by the scientific community in the last 7 years (since 2015) in order to identify new PCs for the GCase enzyme, which have been mainly identified among glycomimetic-based compounds.
σ‑GeH and Germyl Cationic Pt(II) Complexes
(ACS, 2022) Laglera Gándara, Carlos J.; Ríos Moreno, Pablo; Fernández de Córdova, Francisco José; Barturen, Marina; Fernández, Israel; Conejero, Salvador; Universidad de Sevilla. Departamento de Química Inorgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Universidad de Oviedo
The low electron count Pt(II) complexes [Pt(NHC′)(NHC)]- [BArF] (where NHC is a N-heterocyclic carbene ligand and NHC′ its metalated form) react with tertiary hydrogermanes HGeR3 at room temperature to generate the 14-electron platinum(II) germyl derivatives [Pt(GeR3)(NHC)2][BArF]. Low-temperature NMR studies allowed us to detect and characterize spectroscopically some of the σ-GeH intermediates [Pt(η2-HGeR3)(NHC′)(NHC)][BArF] that evolve into the platinum-germyl species. One of these compounds has been characterized by X-ray diffraction studies, and the interaction of the H−Ge bond with the platinum center has been analyzed in detail by computational methods, which suggest that the main contribution is the donation of the H−Ge to a σ*(Pt−C) orbital, but backdonation from the platinum to the σ*(Ge−H) orbital is significant. Primary and secondary hydrogermanes also produce the corresponding platinum-germyl complexes, a result that contrasts with the reactivity observed with primary silanes, in which carbon−silicon bond-forming reactions have been reported. According to density functional theory calculations, the formation of Pt−Ge/C−H bonds is both kinetically and thermodynamically preferred over the competitive reaction pathway leading to Pt−H/C−Ge bonds.
Mechanistic Investigations on Hydrogenation, Isomerization and Hydrosilylation Reactions Mediated by a Germyl-Rhodium System
(Wiley, 2022) Bajo Velázquez, Sonia; Theulier, Cyril A.; Campos, Jesús; Universidad de Sevilla. Departamento de Química Inorgánica; European Research Council (ERC); Junta de Andalucía; European Commission (EC)
We recently disclosed a dehydrogenative double C−H bond activation reaction in the unusual pincer-type rhodium-germyl complex [(ArMes)2ClGeRh] (ArMes=C6H3-2,6-(C6H2-2,4,6-Me3)2). Herein we investigate the catalytic applications of this Rh/Ge system in several transformations, namely trans-semihydrogenation of internal alkynes, trans-isomerization of olefins and hydrosilylation of alkynes. We have compared the activity and selectivity of this catalyst against other common rhodium precursors, as well as related sterically hindered rhodium complexes, being the one with the germyl fragment superior in terms of selectivity towards E-isomers. To increase this selectivity, a tandem catalytic protocol that incorporates the use of a heterogeneous catalyst for the trans-semihydrogenation of internal alkynes has been devised. Kinetic mechanistic investigations provide important information regarding the individual catalytic cycles that comprise the overall trans-semihydrogenation of internal alkynes.
Catalytic Nitrous Oxide Reduction with H2 Mediated by Pincer Ir Complexes
(American Chemical Society, 2022) Ortega Lepe, Isabel; Sánchez Mellado, Práxedes; López Santos, Laura; Lara Muñoz, Patricia; Rendón Márquez, Nuria; López Serrano, Joaquín; Salazar Pereda, Verónica; Álvarez, Eleuterio; Paneque, Margarita; Suárez, Andrés; Universidad de Sevilla. Departamento de Química Inorgánica; Agencia Estatal de Investigación. España; Junta de Andalucía; Consejo Superior de Investigaciones Científicas (CSIC)
Reduction of nitrous oxide (N2O) with H2 to N2 and water is an attractive process for the decomposition of this greenhouse gas to environmentally benign species. Herein, a series of iridium complexes based on proton-responsive pincer ligands (1−4) are shown to catalyze the hydrogenation of N2O under mild conditions (2 bar H2/N2O (1:1), 30 °C). Among the tested catalysts, the Ir complex 4, based on a lutidine-derived CNP pincer ligand having nonequivalent phosphine and N-heterocyclic carbene (NHC) side donors, gave rise to the highest catalytic activity (turnover frequency (TOF) = 11.9 h−1 at 30 °C, and 16.4 h−1 at 55 °C). Insights into the reaction mechanism with 4 have been obtained through NMR spectroscopy. Thus, reaction of 4 with N2O in tetrahydrofuran-d8 (THF-d8) initially produces deprotonated (at the NHC arm) species 5NHC, which readily reacts with H2 to regenerate the trihydride complex 4. However, prolonged exposure of 4 to N2O for 6 h yields the dinitrogen Ir(I) complex 7P, having a deprotonated (at the P- arm) pincer ligand. Complex 7P is a poor catalytic precursor in the N2O hydrogenation, pointing out to the formation of 7P as a catalyst deactivation pathway. Moreover, when the reaction of 4 with N2O is carried out in wet THF-d8, formation of a new species, which has been assigned to the hydroxo species 8, is observed. Finally, taking into account the experimental results, density functional theory (DFT) calculations were performed to get information on the catalytic cycle steps. Calculations are in agreement with 4 as the TOF-determining intermediate (TDI) and the transfer of an apical hydrido ligand to the terminal nitrogen atom of N2O as the TOF-determining transition state (TDTS), with very similar reaction rates for the mechanisms involving either the NHC− or the P−CH2 pincer methylene linkers.
Formic Acid as Renewable Reagent and Product in Biomass Upgrading
(Elsevier, 2023) Achour, Mahdi; Álvarez Hernández, Débora; Ruiz López, Estela; Megías Sayago, Cristina; Ammari, Fatima; Ivanova, Svetlana; Centeno, Miguel Ángel; Universidad de Sevilla. Departamento de Química Inorgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
The problems associated with the use of molecular hydrogen (transportation, storage and high cost) have pushed scientists to the pursuit of efficient hydrogen donors, able to reduce chemical bonds in the presence of catalysts through catalytic transfer hydrogenation (CTH) reactions. In this sense, formic acid stands up as one of the most important and safest chemical molecules for H2 generation under mild conditions. It can be obtained from biomass through different catalytic transformations and used as well to upgrade biomass to platform chemicals. This review summarizes the recently published studies dealing with formic acid production from biomass (using glucose as representing molecule) along with its use in hydrogen involved reactions of different groups of platform chemicals upgrading.
PCNA molecular recognition of different PIP motifs: Role of Tyr211 phosphorylation
(Elsevier, 2024-07) Ruiz Albor, Antonio; Chaves Arquero, Belén; Martín Barros, Inés; Guerra Castellano, Alejandra; González-Magaña, Amaia; Ibáñez de Okapua, Alain; Merino, Nekane; Ferreras Gutiérrez, Mariola; Berra, Edurne; Díaz Moreno, Irene; Blanco, Francisco J.; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Consejo Superior de Investigaciones Científicas (CSIC)
The coordination of enzymes and regulatory proteins for eukaryotic DNA replication and repair is largely achieved by Proliferating Cell Nuclear Antigen (PCNA), a toroidal homotrimeric protein that embraces the DNA duplex. Many proteins bind PCNA through a conserved sequence known as the PCNA interacting protein motif (PIP). PCNA is further regulated by different post-translational modifications. Phosphorylation at residue Y211 facilitates unlocking stalled replication forks to bypass DNA damage repair processes but increasing nucleotide misincorporation. We explore here how phosphorylation at Y211 affects PCNA recognition of the canonical PIP sequences of the regulatory proteins p21 and p15, which bind with nM and μM affinity, respectively. For that purpose, we have prepared PCNA with p-carboxymethyl-L-phenylalanine (pCMF, a mimetic of phosphorylated tyrosine) at position 211. We have also characterized PCNA binding to the non-canonical PIP sequence of the catalytic subunit of DNA polymerase δ (p125), and to the canonical PIP sequence of the enzyme ubiquitin specific peptidase 29 (USP29) which deubiquitinates PCNA. Our results show that Tyr211 phosphorylation has little effect on the molecular recognition of p21 and p15, and that the PIP sequences of p125 and USP29 bind to the same site on PCNA as other PIP sequences, but with very low affinity.
A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
(Elsevier B.V., 2024-10) Mavillard, Fabiola; Guerra Castellano, Alejandra; Guerrero Gómez, David; Rivas, Eloy; Cantero, Gloria; Servián Morilla, Emilia; Folland, Chiara; Ravenscroft, Gianina; Martín, Miguel A.; Miranda Vizuete, Antonio; Cabrera Serrano, Macarena; Díaz Moreno, Irene; Paradas, Carmen; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Instituto de Salud Carlos III; Junta de Andalucía; European Union (UE); Ministerio de Ciencia e Innovación (MICIN). España
Cytochrome-c oxidase (COX) is part of the mitochondrial complex IV (CIV). COX deficiency is usually associated with tRNA variants, and less frequently with variants in COX assembly factors. Mutations in COX subunits encoded by mitochondrial DNA and nuclear DNA are rare, likely because most of them are associated to very severe phenotypes with early lethality. COX18, an assembly factor of CIV, has long been analyzed as a potential cause of mitochondrial disease. To date, only one patient has been identified carrying a homozygous missense variant in COX18, associated with neonatal encephalo-cardiomyopathy and axonal sensory neuropathy. Here, we describe a 40-year-old patient, asymptomatic until 7 months of age, who presented with progressive muscle weakness resembling spinal muscle atrophy type-2, associated with oculofacial apraxia and dysarthric speech. Electrophysiology analysis highlighted a severe sensory-motor neuropathy. Muscle biopsy showed striking and diffuse decreases of COX staining and a substantial reduction of CIV activity. Muscle biopsy showed no raggedred fibers, although ultrastructural mitochondrial alterations were evident. A novel homozygous variant (c.598G>A), located in the last nucleotide of exon 3, was detected in COX18 by whole-exome sequencing, which affected the splicing donor site, as demonstrated by cDNA-seq. The patient fibroblasts express a truncated form of COX18 (COX18Δ112-240) capable of assembling CIV and CIV-involving supercomplexes. However, CIV activity was decreased. COX18 full-length (COX18-fl) overexpression partially rescued CIV activity in the patient fibroblasts. The rescue of the null CIV activity in COX18-KO-HEK293 cells by overexpressing of COX18Δ112-240 was significantly lower than in cells with COX18-fl. In addition, cox-18 downregulation in C. elegans resulted in slow growth and, diminished reduced motility phenotypes and as well as severe fragmentation of the mitochondrial network. Our case expands the phenotypes associated with COX18 variants and supports the pathogenic role of COX18 as the cause of a severe encephaloneuropathy syndrome.
Phosphorylation at the disordered N-end makes HuR accumulate and dimerize in the cytoplasm.
(Oxford University Press, 2024-07-05) Baños Jaime, Blanca; Corrales Guerrero, Laura; Pérez Mejías, Gonzalo; Rejano Gordillo, Claudia M.; Velázquez Campoy, Adrián; Martínez Cruz, Luis Alfonso; Rosa Acosta, Miguel Ángel de la; Díaz Moreno, Irene; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Agencia Estatal de Investigación. España; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Universidad de Sevilla; Ministerio de Educación, Cultura y Deporte (MECD). España
Human antigen R (HuR) is an RNA binding protein mainly involved in maintaining the stability and controlling the translation of mRNAs, critical for immune response, cell survival, proliferation and apoptosis. Although HuR is a nuclear protein, its mRNA translational-related function occurs at the cytoplasm, where the oligomeric form of HuR is more abundant. However, the regulation of nucleo-cytoplasmic transport of HuR and its connection with protein oligomerization remain unclear. In this work, we describe the phosphorylation of Tyr5 as a new hallmark for HuR activation. Our biophysical, structural and computational assays using phosphorylated and phosphomimetic HuR proteins demonstrate that phosphorylation of Tyr5 at the disordered N-end stretch induces global changes on HuR dynamics and conformation, modifying the solvent accessible surface of the HuR nucleo-cytoplasmic shuttling (HNS) sequence and releasing regions implicated in HuR dimerization. These findings explain the preferential cytoplasmic accumulation of phosphorylated HuR in HeLa cells, aiding to comprehend the mechanisms underlying HuR nucleus-cytoplasm shuttling and its later dimerization, both of which are relevant in HuR-related pathogenesis.
SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer
(Elsevier, 2024-03-26) Lachiondo Ortega, Sofia; Rejano Gordillo, Claudia M.; Simon, Jorge; Lopitz Otsoa, Fernando; C. Delgado, Teresa; Mazan Mamczarz, Krystyna; Goikoetxea Usandizaga, Naroa; Velázquez Cruz, Alejandro; Díaz Quintana, Antonio Jesús; Díaz Moreno, Irene; Martínez-Chantar, María Luz; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Ministerio de Ciencia e Innovación (MICIN). España; Instituto de Salud Carlos III; Fundación la Caixa; Consejo Nacional de Ciencia y Tecnología (CONACYT). México; European Union (UE); National Institutes of Health. United States; Junta de Andalucía; Junta de Castilla-León; Gobierno de Navarra; Gobierno Vasco; National Cancer Institute (NCI), NIH. United States
The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.
sp2-Iminosugar Azobenzene O-glycosides: Light-sensitive Glycosidase Inhibitors with Unprecedented Tunability and Switching Factors
(Elsevier, 2024) Rivero Barbarroja, Gonzalo; Padilla Pérez, María del Carmen; Maisonneuve, Stéphane; García Moreno, M. Isabel; Tiet, Ben; Vocadlo, David J.; Xie, Juan; García Fernández, José M.; Ortiz Mellet, Carmen; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; European Cooperation in Science and Technology (COST); Natural Sciences and Engineering Research Council of Canada (NSERC); Universidad de Sevilla
The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and β-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human β-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and β-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.
Speeding-up the Determination of Protein-Ligand Affinities by STD NMR: The Reduced Data Set STD NMR Approach (rd-STD NMR)
(American Chemical Society, 2024-01-02) Rocha, Gabriel; Ramírez Cárdenas, Jonathan; Padilla Pérez, María del Carmen; Walpole, Samuel; Nepravishta, Ridvan; García Moreno, M. Isabel; Sánchez Fernández, Elena Matilde; Ortiz Mellet, Carmen; Angulo, Jesús; Muñoz García, Juan Carlos; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla
STD NMR spectroscopy is a powerful ligand-observed NMR tool for screening and characterizing the interactions of small molecules and low molecular weight fragments with a given macromolecule, identifying the main intermolecular contacts in the bound state. It is also a powerful analytical technique for the accurate determination of protein–ligand dissociation constants (KD) of medium-to-weak affinity, of interest in the pharmaceutical industry. However, accurate KD determination and epitope mapping requires a long series of experiments at increasing saturation times to carry out a full analysis using the so-called STD NMR build-up curve approach and apply the “initial slopes approximation”. Here, we have developed a new protocol to bypass this important limitation, which allows us to obtain initial slopes by using just two saturation times and, hence, to very quickly determine precise protein–ligand dissociation constants by STD NMR.
Atroposelective Synthesis of 2-(Quinolin-8-yl)benzyl Alcohols by Biocatalytic Dynamic Kinetic Resolutions
(Wiley, 2023-12-22) Coto Cid, Juan Manuel; Gonzalo Calvo, Gonzalo de; Carmona, José A.; Iglesias Sigüenza, Francisco Javier; Rodríguez Salamanca, Patricia; Fernández Fernández, Rosario Fátima; Hornillos, Valentín; Lassaletta, José M.; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
A highly enantioselective biocatalytic dynamic kinetic resolution (DKR) of 2-(quinoline-8-yl) 3-methylbenzaldehydes and 1-naphthaldehydes is described. The reaction proceeds by atroposelective carbonyl reduction catalyzed by commercial ketoreductases (KREDs), generally reaching high conversions and excellent enantiomeric excesses. Both atropoisomers of the final alcohols can be obtained by a proper selection of the biocatalyst. The DKR strategy relies in the racemization of the stereogenic axis that takes place thanks to a transient Lewis acid-base interaction (LABI) between the nitrogen in the quinoline and the carbonyl group.
Enzyme-Responsive Zr-Based Metal-Organic Frameworks for Controlled Drug Delivery: Taking Advantage of Clickable PEG-Phosphate Ligands
(American Chemical Society, 2023) Carrillo Carrión, Carolina; Comaills, Valentine; Visiga, Ana M.; Gauthier, Benoit R.; Khiar, Noureddine; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Asociación Española Contra el Cáncer; Marie Sklodowska-Curie Individual Fellowship; European Cooperation in Science and Technology (COST)
We report for the first time the controlled drug release from a nanoscale Zr-based metal-organic framework (MOF), UiO-66, in the presence of the enzyme alkaline phosphatase (ALP). This unprecedented reactivity was possible thanks to the prior functionalization of the MOF with N3-PEG-PO3 ligands, which were designed for three specific aims: (1) to impart colloidal stability in phosphate-containing media; (2) to endow the MOF with multifunctionality thanks to azide groups for the covalent attachment of an imaging agent by click-chemistry; and (3) to confer stimuli-responsive properties, specifically the selective release of doxorubicin triggered by the enzymatic activity of ALP. Cell studies revealed that the functionalization of the MOF with N3-(PEG)20-PO3 ligands improved their intracellular stability and led to a sustained drug release compared to the bare MOF. More importantly, an enhanced drug release was observed in cells with higher expression of ALP genes (HeLa versus MDA-MB-231 and MCF7), confirming the ALP-responsiveness of the system inside living cells.

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