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María Angeles Pajares

María Angeles Pajares
Centro de Investigaciones Biológicas Margarita Salas · Dept. Structural and Chemical Biology

PhD
Guest editing a Special Issue on "Amino Acid Metabolism and Disease" in the International Journal of Molecular Sciences

About

117
Publications
11,738
Reads
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3,357
Citations
Introduction
María Ángeles Pajares currently works at the Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas (CSIC). María does research in Cell Biology, Molecular Biology and Structural Biology. Her current projects are 'Regulation of the methionine cycle' and 'Post-translational protein modifications'.
Additional affiliations
January 2017 - present
Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC) Madrid, Spain
Position
  • Senior Researcher
January 2007 - February 2017
Universidad Autónoma de Madrid
Position
  • Professor
June 2006 - January 2017
Institute for Biomedical Research “Alberto Sols“ (CSIC-UAM), Madrid, Spain
Position
  • Senior Researcher
Education
July 1983 - June 1986
Complutense University of Madrid
Field of study
  • Biological Sciences
September 1977 - June 1983
Complutense University of Madrid
Field of study
  • Biological Sciences

Publications

Publications (117)
Article
Full-text available
The intermediate filament protein vimentin plays a key role in cell signaling and stress sensing, as well as an integrator of cytoskeletal dynamics. The vimentin monomer consists of a central rod-like domain and intrinsically disordered head and tail domains. Although the organization of vimentin oligomers in filaments is beginning to be understood...
Article
Full-text available
The SARS-CoV-2 Spike protein mediates docking of the virus onto cells prior to viral invasion. Several cellular receptors facilitate SARS-CoV-2 Spike docking at the cell surface, of which ACE2 plays a key role in many cell types. The intermediate filament protein vimentin has been reported to be present at the surface of certain cells and act as a...
Article
Full-text available
Allergic reactions to antibiotics are a major concern in the clinic. ß -lactam antibiotics are the class most frequently reported to cause hypersensitivity reactions. One of the mechanisms involved in this outcome is the modification of proteins by covalent binding of the drug (haptenation). Hence, interest in identifying the corresponding serum an...
Article
Full-text available
This work analyzes the role of polar interactions at the dimer-dimer interface of MAT I to sustain the momo-tetramer. The results highlight how the few polar interactions established through residues on loops at both sides of the beta-sheet of the central domain, and the alpha-helix behind, influence asociation. Human mutations in this area could f...
Article
Full-text available
The intermediate filament protein vimentin is involved in essential cellular processes, including cell division and stress responses, as well as in the pathophysiology of cancer, pathogen infection, and autoimmunity. The vimentin network undergoes marked reorganizations in response to oxidative stress, in which modifications of vimentin single cyst...
Preprint
The Spike protein from SARS-CoV-2 mediates docking of the virus onto cells and contributes to viral invasion. Several cellular receptors are involved in SARS-CoV-2 Spike docking at the cell surface, including ACE2 and neuropilin. The intermediate filament protein vimentin has been reported to be present at the surface of certain cells and act as a...
Preprint
Full-text available
The intermediate filament protein vimentin is involved in essential cellular processes, including cell division and stress responses. Vimentin oxidative modifications impact network reorganization and its single cysteine residue, Cys328, acts as a redox sensor. Vimentin binds zinc, which influences its assembly by undefined mechanisms. Here, result...
Article
Full-text available
Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational modifications. The type III IFs, vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP), are targets for diverse modifications by oxidants and electrophiles, for which their...
Article
Introduction Age-related hearing loss (ARHL) is a sensory impairment, with a dramatic increase in its incidence, which is caused by genetic and environmental factors such as noise and ototoxic drugs. Recent studies correlated ARHL to elevated plasma homocysteine (Hcy) by folate deficiency, suggesting that reduction of Hcy levels by folate supplemen...
Article
Full-text available
Serum and cellular proteins are targets for the formation of adducts with the β-lactam antibiotic amoxicillin. This process could be important for the development of adverse, and in particular, allergic reactions to this antibiotic. In studies exploring protein haptenation by amoxicillin, we observed that reducing agents influenced the extent of am...
Article
Full-text available
Enzymes of the methionine and homocysteine metabolism catalyze reactions belonging to the methionine and folate cycles and the transsulfuration pathway. The importance of the metabolites produced through these routes (e.g. S-adenosylmethionine, homocysteine) and their role in e.g. epigenetics or redox mechanisms makes their tight regulation essenti...
Article
Full-text available
The vimentin network displays remarkable plasticity to support basic cellular functions and reorganizes during cell division. Here, we show that in several cell types vimentin filaments redistribute to the cell cortex during mitosis, forming a robust framework interwoven with cortical actin and affecting its organization. Importantly, the intrinsic...
Preprint
Full-text available
Serum and cellular proteins are targets for the formation of adducts with the β-lactam antibiotic amoxicillin. This process could be important for the development of adverse, and in particular, allergic reactions to this antibiotic. In studies exploring protein haptenation by amoxicillin, we observed that reducing agents influenced the extent of am...
Article
Full-text available
The intermediate filament protein vimentin constitutes a critical sensor for electrophilic and oxidative stress, which induce extensive reorganization of the vimentin cytoskeletal network. Here, we have investigated the mechanisms underlying these effects. In vitro, electrophilic lipids, including 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and 4-h...
Article
Protein modification by lipid derived reactive species, or lipoxidation, is increased during oxidative stress, a common feature observed in many pathological conditions. Biochemical and functional consequences of lipoxidation include changes in the conformation and assembly of the target proteins, altered recognition of ligands and/or cofactors, ch...
Article
Betaine homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine, hence their malfunction leads to hyperhomocysteinemia. Epidemiological and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the...
Article
Full-text available
Hearing loss has been recently ranked as the fifth leading cause of years lived with disability, ahead of many other chronic diseases such as diabetes, dementia, or chronic obstructive pulmonary disease. Moreover, according to the World Health Organization, moderate-to-profound hearing loss affects about 466 million people worldwide. Its incidence...
Preprint
Full-text available
The vimentin network displays remarkable plasticity to support basic cellular functions. Here, we show that in several cell types vimentin filaments redistribute to the cell periphery during mitosis, forming a robust scaffold interwoven with cortical actin and affecting the mitotic cortex properties. Importantly, the intrinsically disordered tail d...
Article
Full-text available
Protein-protein interactions are an important mechanism for the regulation of enzyme function allowing metabolite channeling, crosstalk between pathways or the introduction of post-translational modifications. Therefore, a number of high-throughput studies have been carried out to shed light on the protein networks established under different patho...
Article
Asthma and rhinitis are two of the main clinical manifestations of allergy, in which increased reactive oxygen or electrophilic species can play a pathogenic role. Aldose reductase (AKR1B1) is involved in aldehyde detoxification and redox balance. Recent evidence from animal models points to a role of AKR1B1 in asthma and rhinitis, but its involvem...
Chapter
The methionine cycle synthesizes S-adenosylmethionine, the main cellular methyl donor. Regulation of the methionine cycle is exerted at several levels from transcription up to subcellular localization. The liver is the major organ for methionine consumption and metabolization. The methionine cycle also produces S-adenosylhomocysteine and homocystei...
Article
Significance: Transsulfuration allows conversion of methionine into cysteine using homocysteine as an intermediate. This pathway produces S-adenosylmethionine, a key metabolite for cell function, and provides 50% of the cysteine needed for hepatic glutathione synthesis. The route requires the intake of essential nutrients (e.g. methionine, vitamin...
Article
Full-text available
PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the PDRG1 gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular...
Article
Full-text available
Hearing loss (HL) is one of the most common causes of disability, affecting 360 million people according to the World Health Organization (WHO). HL is most frequently of sensorineural origin, being caused by the irreversible loss of hair cells and/or spiral ganglion neurons. The etiology of sensorineural HL (SNHL) is multifactorial, with genetic an...
Article
The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in mainte...
Article
Full-text available
Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after 2-months, corroborates the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation fol...
Article
Full-text available
Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular...
Data
Heatmaps of microarray results for relevant pathways according to BioProfiling analysis. The figure highlights expression results of genes identified with BioProfiling (p≤0.01). The pathways including these genes are: Response to starvation (GO: 0042594); Lipid metabolic process (GO: 0006629); Liver development (GO:0001889); Extracellular space (GO...
Data
Pdrg1 expression levels in transient transfections using shRNA plasmids. H35 cells were transiently transfected for 48 hours with shRNA plasmids harboring sequences for Pdrg1 silencing (shRNA1-4) and a negative control (CN). Transfected cells were selected for 2 weeks with 1.8 mg/ml G418. Expression levels were analyzed by real-time RT-PCR using ap...
Data
PDRG1 levels in hepatic nuclear fractions of D-galactosamine intoxicated rats. Subcellular fractions of the whole liver from control (N = 4) and D-galactosamine (N = 6) intoxicated rats were analyzed by western blotting. Lamin B1 levels were used as reference, whereas tubulin signals were used to establish cross-contamination with cytosolic fractio...
Data
Graphical representation of microarray differential expression changes. Microarray expression data were analyzed with FIESTA Viewer to identify genes exhibiting changes ≥2-fold with FDR<0.05. These data were used for clustering and preparation of heatmaps using Cluster and Java TreeView, respectively. The figure shows results (N = 4) of up- and dow...
Data
Expression of Mat genes evaluated by real-time RT-PCR in stable clones. CN-10, 3-44-and 4–18 stable clones (N = 4) were used to analyze putative effects of Pdrg1 silencing on Mat1a and Mat2a expression using RTqPCR and appropriate TaqMan probes. The figure shows the mean ± SEM of measurements carried out in triplicate, where expression changes were...
Data
Comparison of microarray results versus CN-10. The table shows expression changes for stable clones 4–18 and 3–44 and the transient pool shRNA3T versus CN-10. Upregulated genes (≥ 2) and downregulated genes (≤ -2) are listed separately. (XLS)
Article
Full-text available
Phase I and II enzymes are involved in the metabolism of endogenous reactive compounds as well as xenobiotics, including toxicants and drugs. Genotyping studies have established several drug metabolizing enzymes as markers for risk of drug hypersensitivity. However, other candidates are emerging that are involved in drug metabolism but also in the...
Article
Full-text available
S-adenosylmethionine is a very versatile compound known to be involved in as many reactions as ATP. Its role as methyl donor is key for the production of a large variety of molecules, as well as, for the modification of proteins and nucleic acids. Therefore, it is not surprising that impairments in the methionine cycle are found in many diseases in...
Article
Full-text available
Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low s...
Article
Full-text available
Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impa...
Article
Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well-known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low s...
Article
Full-text available
Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels...
Article
S-adenosylmethionine synthesis is a key process for cell function, and needs to be regulated at multiple levels. In recent years, advances in the knowledge of methionine adenosyltransferases have been significant. The discovery of nuclear localization of these enzymes suggests their transport to provide the methyl donor, S-adenosylmethionine, for D...
Article
Glutathione S transferase P1-1 plays a key role in the metabolism of inflammatory mediators and drugs, thus modulating the inflammatory response. Active GSTP1-1 is a homodimer with cysteine residues close to the active site that can undergo oligomerization in response to stress, a process that affects enzyme activity and interactions with signaling...
Article
Betaine homocysteine S-methyltransferase (BHMT, EC 2.1.1.5) is one of the two enzymes known to methylate homocysteine (Hcy) to generate methionine in the liver. The increase in plasma levels of Hcy (homocysteine) has been established as an independent risk factor for cardiovascular and Alzheimer diseases. BHMT uses betaine as the methyl donor to sy...
Article
Full-text available
Mammalian methionine adenosyltransferase II (MAT II) is the only hetero-oligomer in this family of enzymes that synthesize S-adenosylmethionine using methionine and ATP as substrates. Binding of regulatory β subunits and catalytic α2 dimers is known to increase the affinity for methionine, although scarce additional information about this interacti...
Article
Methionine metabolism is impaired in patients with liver damage and this alteration might complicate and maintain the clinical syndrome. Alterations in this pathway are associated with a defect in S-adenosyl-L-methionine (SAMe) synthetase activity. Liver glutathione, which is derived from SAMe via the transsulphuration pathway, is also depleted as...
Article
Methionine adenosyltransferase from Euglena gracilis (MATX) is a recently discovered member of the MAT family of proteins that synthesize S-adenosylmethionine. Heterologous overexpression of MATX in Escherichia coli rendered the protein mostly in inclusion bodies under all conditions tested. Therefore, a refolding and purification procedure from th...
Article
Methionine adenosyltransferases (MATs) are a family of highly conserved oligomers that catalyze the only known reaction for the synthesis of S-adenosylmethionine (AdoMet), the main cellular methyl donor. Their catalytic subunits exhibit a characteristic structure, organized in three domains formed by nonconsecutive stretches of the sequence. The ac...
Article
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Departamento de Bioquímica. Fecha de lectura: 23 de Febrero de 2009
Article
Full-text available
The methionine adenosyltransferase from the thermophile Methanococcus jannaschii is fully and irreversibly unfolded in the presence of guanidinium chloride. Unfolding of this dimeric protein is a three-state process in which a dimeric intermediate could be identified. The less stable secondary structural elements of the protein are the C-terminal e...
Article
Full-text available
Glutathione transferase P1-1 (GSTP1-1) plays crucial roles in cancer chemoprevention and chemoresistance and is a key target for anticancer drug development. Oxidative stress or inhibitor-induced GSTP1-1 oligomerization leads to the activation of stress cascades and apoptosis in various tumor cells. Therefore, bivalent glutathione transferase (GST)...
Article
Archaea contain a class of methionine adenosyltransferases (MATs) that exhibit substantially higher stability than their mesophilic counterparts. Their sequences are highly divergent, but preserve the essential active site motifs of the family. We have investigated the origin of this increased stability using chemical denaturation experiments on Me...
Article
Full-text available
The methyl donor S-adenosylmethionine is synthesized in mammalian cytosol by three isoenzymes. Methionine adenosyltransferase II is ubiquitously expressed, whereas isoenzymes I (homotetramer) and III (homodimer) are considered the hepatic enzymes. In this work, we identified methionine adenosyltransferase I/III in most rat tissues, both in the cyto...
Article
Full-text available
Methionine adenosyltransferases (MATs) are the family of enzymes that synthesize the main biological methyl donor, S-adenosylmethionine. The high sequence conservation among catalytic subunits from bacteria and eukarya preserves key residues that control activity and oligomerization, which is reflected in the protein structure. However, structural...
Article
Full-text available
Wilson's disease is characterized by longterm hepatic accumulation of copper leading to liver disease with reduction of S-adenosylmethionine synthesis. However, the initial changes in this pathway remain unknown and constitute the objective of the present study. Using the Long Evans Cinnamon rat model, early alterations were detected in the mRNA an...
Article
Full-text available
Betaine homocysteine methyltransferase (BHMT), a Zn(2+)-dependent thiolmethyltransferase, contributes to the regulation of homocysteine levels, increases in which are considered a risk factor for cardiovascular diseases. Most plasma homocysteine is generated through the liver methionine cycle, in which BHMT metabolizes approximately 25% of this non...
Article
Full-text available
Equilibrium folding of rat liver BHMT (betaine-homocysteine methyltransferase), a TIM (triosephosphate isomerase)-barrel tetrameric protein, has been studied using urea as denaturant. A combination of activity measurements, tryptophan fluorescence, CD and sedimentation-velocity studies suggested a multiphasic process including two intermediates, a...
Article
Two-dimensional infrared spectroscopy has been used to characterize rat liver methionine adenosyltransferase and the events taking place during its thermal unfolding. Secondary structure data have been obtained for the native recombinant enzyme by fitting the amide I band of infrared spectra. Thermal denaturation studies allow the identification of...
Article
Betaine homocysteine S-methyltransferase (BHMT) is one of the two enzymes known to methylate homocysteine to generate methionine in the liver. It presents a Zn(2+) atom linked to three essential Cys residues. The crystal structure of rat liver BHMT has been solved at 2.5A resolution, using crystals with P2(1) symmetry and 45% solvent content in the...