El "guardià del genoma" i la proteïna PIG3

La proteïna supressora de tumors p53, anomenada "guardià del genoma", regula l'expressió d'un gran nombre de gens, entre ells el gen PIG3, que participen en l'aturada de la divisió cel·lular, en la reparació del DNA i en l'apoptosi o mort cel·lular programada. La proteïna expressada per aquest gen, també anomenada PIG3, era poc coneguda i, des del Departament de Bioquímica i Biologia Molecular, s'ha caracterizat la seva funció enzimàtica. Una de les dues activitats enzimàtiques identificades és la quinona reductasa responsable de la generació de peròxid d'hidrogen, la qual cosa indueix la mort cel·lular. Aquests procesos estan implicats en l'origen de múltiples malaties, com el càncer, immunodeficiències o malalties degeneratives.La proteína supresora de tumores p53, llamada "guardián del genoma", regula la expresión de una gran número de genes, entre ellos el gen PIG3, que participan en la parada de la división celular, en la reparación del DNA y en la apoptosis o muerte celular programada. La proteína expresada por este gen, también llamada PIG3, era poco conocida y, desde el Departament de Bioquímica i Biologia Molecular se ha caracterizado su función enzimática. Una de las dos actividades enzimáticas es la quinona reductasa, responsable de la generación de peróxido de hidrógeno, lo cual induce la muerte celular. Estos procesos están implicados en el origen de múltiples enfermedades, como el cáncer, inmunodeficiencias o enfermedades degenerativas

Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling

Several aldo–keto reductase (AKR) enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low Km and kcat values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3), as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA) biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in β-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance

Error de inclinación paleomagnética en materiales aluviales del Oligoceno superior del sector Suroriental de la Cuenca del Ebro (Región Surpirenaica, NE de España)

Alluvial red-beds of two Oligocene succesions in the Southeastem Ebro Basin (Southem Pyrenean foreland, NE Spain) show inclination shallowing, taking into account the reference Oligocene palaeolatitude expected for this region. This fact is interpreted to reflect an inclination error due to either these factors: hydrodynamic control of magnetic particles in the depositional environment, differential compaction of sediment during burial and tectonic deformation. The studied lithofacies are split into five groups: gray sandstones, red sandstones, red siltstones, red mudstones and limestones. A strong positive correlation between the relative amount of phyllosilicates and the magnitude of the inclination error has been established. Lithofacies with low percentage of phyllosilicates (limestones and gray sandstones) display a statistically not significant error of 5" with respect to the magnetic palaeofield inclination, whereas the sediments with a higher phyllosilicate content (siltstones and mudstones) show significant errors of up to 25". This observation has not a major consequence for the interpretation of the magnetic polarity but is crucial for palaeogeographic and palinspastic reconstmctions based on palaeolatitudinal data. The obtained results in this study highlight that the interpretation of paleolatitude based on paleomagnetic data is sometimes not straightfonvard and it requires a detailed evaluation of the rock magnetic parameters (AMS in particular) to reveal the presence of such inclination deflection

Enzims del metabolisme de l'alcohol

La sospita d'una predisposició genètica a l'alcoholisme ha aixecat una gran quantitat de recerques per confirmar-l

Online structural damage classification methodology for offshore wind turbine foundations using data stream analysis

Structural health monitoring (SHM) of wind turbines is crucial to improve maintenance and extend their lifespan. This study develops an online data analysis methodology using data stream analysis to classify damage in the links of an offshore wind turbine foundation. The methodology is validated using a laboratory-scaled jacket-type wind turbine foundation structure. 2460 measurements of the healthy structure were acquired, and a 5mm crack was applied to four different links to determine the four unhealthy classes. 820 measurements were taken for each of the unhealthy structures, resulting in a dataset with 5740 instances. As this is an imbalanced multiclass classification problem, a random sampler approach was used to treat the data. The only data obtained was from eight triaxial accelerometers distributed throughout the structure. Three different tree-based stream data classifiers were compared: Hoeffding Tree classifier, Extremely Fast Decision Tree classifier, and Hoeffding Adaptive Tree classifier. Each classification model underwent a tuning parameter procedure, and high values of the receiving operating characteristic area under the curve (ROC AUC) metric were achieved as a result. It is important to note that stream learning differs from batch learning.Peer ReviewedPostprint (published version

Structural and biochemical evidence that ATP inhibits the cancer biomarker human aldehyde dehydrogenase 1A3

Human aldehyde dehydrogenase (ALDH) participates in the oxidative stress response and retinoid metabolism, being involved in several diseases, including cancer, diabetes and obesity. The ALDH1A3 isoform has recently elicited wide interest because of its potential use as a cancer stem cell biomarker and drug target. We report high-resolution three-dimensional ALDH1A3 structures for the apo-enzyme, the NAD+ complex and a binary complex with ATP. Each subunit of the ALDH1A3-ATP complex contains one ATP molecule bound to the adenosine-binding pocket of the cofactor-binding site. The ATP complex also shows a molecule, putatively identified as a polyethylene glycol aldehyde, covalently bound to the active-site cysteine. This mimics the thioacyl-enzyme catalytic intermediate, which is trapped in a dead enzyme lacking an active cofactor. At physiological concentrations, ATP inhibits the dehydrogenase activity of ALDH1A3 and other isoforms, with a Ki value of 0.48 mM for ALDH1A3, showing a mixed inhibition type against NAD+. ATP also inhibits esterase activity in a concentration-dependent manner. The current ALDH1A3 structures at higher resolution will facilitate the rational design of potent and selective inhibitors. ATP binding to ALDH1A3 enables activity modulation by the energy status of the cell and metabolic reprogramming, which may be relevant in several disease conditions

Class IV mammalian alcohol dehydrogenase Structural data of the rat stomach enzyme reveal a new class well separated from those already characterized

AbstractThe stomach form of alcohol dehydrogenase has been structurally evaluated by peptide analysis covering six separate regions of the rat enzyme. Overall, this new structure diners widely (32–40% residue differences) from the structures of three classes of alcohol dehydrogenase characterized before from the same species. Consequently, this novel enzyme constitutes a true fourth class of mammalian alcohol dehydrogenase. In particular, differences are extensive also towards class II, although enzymatic and physicochemical properties initially suggested overall similarities with class II. The new structure establishes the presence of one further alcohol dehydrogenase mammalian gene, extends the enzyme family derived from repeated gene duplications, and confirms tissue-specific expressions