Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process. The estrogens are necessary in humans, mainly in women, because of the role they play in sexual and reproductive development. However, these also are involved in the development and growth of hormone-dependent breast cancer. Therefore, inhibition of the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers. Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in breast cancer treatment. In this study, the hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/ mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage, suggesting a possible competitive mechanism between the inhibitor and the natural substrate androstenedione in the first catalytic subcycle of the enzyme. Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site shows that the role of the enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects

The extra virgin olive oil phenolic oleacein is a dual substrate-inhibitor of catechol-O-methyltransferase

Catechol-containing polyphenols present in coffee and tea, while serving as excellent substrates for catechol-Omethyltransferase (COMT)-catalyzed O-methylation, can also operate as COMT inhibitors. However, little is known about the relationship between COMT and the characteristic phenolics present in extra virgin olive oil (EVOO). We here selected the EVOO dihydroxy-phenol oleacein for a computational study of COMT-driven methylation using classic molecular docking/molecular dynamics simulations and hybrid quantum mechanical/ molecular mechanics, which were supported by in vitro activity studies using human COMT. Oleacein could be superimposed onto the catechol-binding site of COMT, maintaining the interactions with the atomic positions involved in methyl transfer from the S-adenosyl-L-methionine cofactor. The transition state structure for the meta-methylation in the O5 position of the oleacein benzenediol moiety was predicted to occur preferentially. Enzyme analysis of the conversion ratio of catechol to O-alkylated guaiacol confirmed the inhibitory effect of oleacein on human COMT, which remained unaltered when tested against the protein version encoded by the functional Val158Met polymorphism of the COMT gene. Our study provides a theoretical determination of how EVOO dihydroxy-phenols can be metabolized via COMT. The ability of oleacein to inhibit COMT adds a new dimension to the physiological and therapeutic utility of EVOO secoiridoids

Colecciones ex situ de planta viva para la conservación de la planta amenazada Silene hifacensis, Rouy ex Willk (Caryophyllaceae)

The establishment of seed orchards has allowed obtaining a great deal of germoplasm of Silene hifacensis, an endangered endemic Ibero-Balearic species. In four years, 3.958.531 seeds have been collected in our four seed orchards from a total of 570 plants/year per average, including all genetic variability from natural populations of this species in Alicante province (Illot of Mona, the Pessebret, Cova de les Cendres, Morro de Toix)

A theoretical study on the mechanism of the oxidation of substrates by human aromatase enzyme (CYP19A1)

The enzyme Cytochrome P450 aromatase plays an essential role in the biosynthesis of estrogens, and its inhibition is an important target for the development of drugs for the treatment of breast cancer. The main purpose of the present thesis is to improve the understanding of the catalytic mechanism and the biochemistry of this enzyme from the standpoint of theoretical chemistry. The results of this thesis have been divided into three main sections: (1) Study of the reactive species of the enzyme aromatase: Compound I; (2) Study of the hydroxylation of the natural substrate androstenedione, during the first catalytic subcycle of the enzyme aromatase; and (3) Study of the hydroxylation of Exemestane, an esteroidal third generation aromatase inhibitor, currently used in hormone dependent breast cancer therapy.La enzima citocromo P450 aromatasa juega un papel esencial en la biosíntesis de estrógenos, y su inhibición es un objetivo importante para el desarrollo de medicamentos para el tratamiento del cáncer de mama. El objetivo principal de la esta Tesis ha sido arrojar luz sobre el mecanismo catalítico y sobre la bioquímica de esta enzima, desde el punto de vista de la química teórica. Los resultados que se presentan en esta Tesis se han dividido en tres secciones principales: (1) Estudio de la especie reactiva de la enzima aromatasa: "Compound I"; (2) Estudio de la hidroxilación del substrato natural androstenediona, a lo largo del primer subciclo catalítico de esta enzima; y (3) Estudio de la hidroxilación del Exemestano, un inhibidor esteroideo de tercera generación de la enzima aromatasa, que se utiliza actualmente en el tratamiento del cáncer de mama hormonodependiente

Anàlisi i vaoració de la empresa Mercadona SA.

[ES] El Trabajo de Fin de Grado (TFG) en ADE ha sido realizado con el objetivo de diagnosticar la situación de Mercadona y realizar una valoración exhaustiva de la empresa para lo cual se ha utilizado diferentes herramientas de análisis estratégico. Entre las herramientas utilizadas se encuentran el análisis DAFO, el PORTER y el PESTEL, las cuales se enfocan en analizar los aspectos internos y externos de la empresa, así como las fuerzas y debilidades del mercado. Además, se han utilizado ratios y estructuras analíticas en el análisis económico-financiero de la empresa. Para la valoración de Mercadona, se han utilizado los dos métodos más conocidos en la valoración de empresas: el método de múltiplos y el descuento de flujos de caja. Estos métodos permiten analizar la rentabilidad de la empresa y proyectar su crecimiento futuro, lo que resulta fundamental para la toma de decisiones estratégicas. En definitiva, el TFG ha utilizado un conjunto de herramientas y métodos para lograr una evaluación exhaustiva de la situación de Mercadona. Además de las herramientas y métodos mencionados, en el análisis de Mercadona también se han utilizado algunas expresiones propias del lenguaje de la empresa, como "El Jefe" (el cliente), "Surtido eficaz" (una de las estrategias clave de Mercadona) y "La Excelencia" (uno de los valores fundamentales de la empresa). También se han analizado aspectos como la política de precios bajos, la gestión de la cadena de suministro y la importancia de la innovación en la estrategia de Mercadona.[EN] The Final Degree Project (TFG) in ADE has been carried out with the aim of diagnosing the situation of Mercadona and making an exhaustive assessment of the company, for which different strategic analysis tools have been used. Among the tools used are the SWOT, PORTER and PESTEL analyses, which focus on analyzing the internal and external aspects of the company, as well as the strengths and weaknesses of the market. In addition, ratios and analytical structures have been used in the economic-financial analysis of the company. For the valuation of Mercadona, the two most well-known methods in the valuation of companies have been used: the multiples method and the discounted cash flow method. These methods make it possible to analyze the company's profitability and project its future growth, which is essential for strategic decision-making. In short, the TFG has used a set of tools and methods to achieve a comprehensive assessment of Mercadona's situation. In addition to the aforementioned tools and methods, the analysis of Mercadona has also used some expressions typical of the company's language, such as "The Boss" (the customer), "Efficient assortment" (one of Mercadona's key strategies) and "Excellence" (one of the company's fundamental values). Aspects such as the low price policy, supply chain management and the importance of innovation in Mercadona's strategy were also analyzed.Viciano Claramunt, I. (2023). Análisis y valoración de la empresa Mercadona, S.A. Universitat Politècnica de València. http://hdl.handle.net/10251/19624

Proyecto para el aumento del catálogo de basura espacial: priorización y coordinación de observacionesProyecto para el aumento del catálogo de basura espacial: priorización y coordinación de observaciones

[ES] Los "Two-Line Element sets" son un formato de datos en el que se codifica la información sobre todos los objetos conocidos en órbita terrestre. Los archivos TLE se usan junto con un modelo de perturbaciones simplificado, como el SGP4, para obtener la posición y la velocidad de los objetos en un momento dado, publicado por el North American Aerospace Defense Command (NORAD). Este proyecto busca desarrollar las herramientas necesarias para mejorar los TLE utilizando la cooperación de la comunidad de Astrónomos Amateur, ya que aumentar la cantidad de información reducirá los errores debidos a la propagación de las órbitas a lo largo del tiempo. Para ello, se aplican varias limitaciones geométricas: para ser visto un objecto, la observación debe ocurrir durante la noche y el objeto debe estar iluminado por el Sol y a una elevación razonable. Se ha calculado cómo, para un ejemplo de 12.668 satélites de un determinado archivo TLE, 391 pudieron ser observados desde una posición y una época seleccionadas. Los errores del propagador son una preocupación, por lo que los datos históricos de una gran colección de objetos han sido procesados, mostrando cómo las principales imprecisiones del modelo SGP4 ocurren en la dirección de la velocidad y para las órbitas de alta altitud. Para asegurarse de que un objeto particular es capturado, el análisis estadístico de los datos históricos se utilizará para coordinar diferentes observaciones.[EN] The Two-Line Element sets are a data format in which the information about all the largest Earth-orbiting objects is encoded. Published by the North American Aerospace Defense Command (NORAD), the TLE files are used along with a simplified perturbation model, such as the SGP4, in order to obtain the position and velocity of the objects at a given time. This project seeks to develop the necessary tools to enhance the TLEs for Earth orbiting debris using the cooperation of the Amateur Astronomer community, as increasing the amount of information will reduce the errors due to the propagation of the orbits along time. For that, several geometrical constraints are applied: to be seen, the observation must occur at nighttime and the object illuminated by the Sun and at a reasonable elevation. It has been calculated how, for 13,309 satellites of a given TLEs file, 380 were able to be observed from a selected position and epoch. Errors from the propagator are a concern, so historical data of a large collection of objects has been processed, showing how the main inaccuracies of the SGP4 model occur in the velocity direction and for high altitude orbits. To make sure that a particular object is captured, statistical analysis of historical data will be used to coordinate different observations.Viciano Semper, IE. (2017). Debris catalog augmentation project: prioritization and coordination of the observations. Universitat Politècnica de València. http://hdl.handle.net/10251/144141TFG

Sistema electrónico de control de un dirigible basado en un microcontrolador de 32 bits

En este Trabajo Final de Grado se ha desarrollado un sistema electrónico para el control del un dirigible autónomo. Para este propósito ha sido fundamental obtener tanto la actitud de la aeronave (cabeceo, alabeo y guiñada) como su posición y velocidad, y desarrollar una plataforma capaz de evaluar y recoger todos los datos necesarios para generar las acciones de control correspondientes. Esta plataforma electrónica será utilizada para la implementación del control automático por parte de Daniel Orient en su Trabajo Final de Grado Modelo dinámico y diseño del sistema de control para un zeppelin autónomo. Se ha utilizado la placa STM32F3 Discovery, que tiene, entre otros componentes, un microcontrolador de 32 bits y una Unidad de Medición Inercial. Además también se han necesitado para el proyecto un móulo de ultrasonidos, un GPS y un barómetro, con el fin de caracterizar completamente el dirigible. Para llevar todo esto a cabo se han utilizado los softwares CoIDE by Coocox, para programar el microcontrolador con C, y MATLAB, para analizar los resultados y crear una interfaz gráfica útil y capaz de llevar a cabo el control del dirigible. Además se han realizado otras tareas imprescindibles para el Trabajo tales como el filtrado de la información, la implementación de las interfaces de comunicación (I2C, SPI y USART), la gestión de los temporizadores e interrupciones del microcontrolador y la generación de las señales PWM para el control de los motores. Este Trabajo Final de Grado abarca muchas horas de trabajo tanto de experimentación en el laboratorio como de documentación. Se espera que sea útil para otros proyectos futuros, ya que no sólo se expondrá el resultado final sino los problemas que han surgido y cómo se han solucionado.Viciano Semper, IE. (2015). Sistema electrónico de control de un dirigible basado en un microcontrolador de 32 bits. Universitat Politècnica de València. http://hdl.handle.net/10251/54679Archivo delegad

New insight into the electronic structure of iron(IV)-oxo porphyrin compound I. A quantum chemical topological analysis

The electronic structure of iron-oxo porphyrin π-cation radical complex Por·+FeIV[DOUBLE BOND]O (S[BOND]H) has been studied for doublet and quartet electronic states by means of two methods of the quantum chemical topology analysis: electron localization function (ELF) η(r) and electron density ρ(r). The formation of this complex leads to essential perturbation of the topological structure of the carbon–carbon bonds in porphyrin moiety. The double C[DOUBLE BOND]C bonds in the pyrrole anion subunits, represented by pair of bonding disynaptic basins Vi=1,2(C,C) in isolated porphyrin, are replaced by single attractor V(C,C)i=1–20 after complexation with the Fe cation. The iron–nitrogen bonds are covalent dative bonds, N→Fe, described by the disynaptic bonding basins V(Fe,N)i=1–4, where electron density is almost formed by the lone pairs of the N atoms. The nature of the iron–oxygen bond predicted by the ELF topological analysis, shows a main contribution of the electrostatic interaction, Feδ+···Oδ−, as long as no attractors between the C(Fe) and C(O) core basins were found, although there are common surfaces between the iron and oxygen basines and coupling between iron and oxygen lone pairs, that could be interpreted as a charge-shift bond. The Fe[BOND]S bond, characterized by the disynaptic bonding basin V(Fe,S), is partially a dative bond with the lone pair donated from sulfur atom. The change of electronic state from the doublet (M = 2) to quartet (M = 4) leads to reorganization of spin polarization, which is observed only for the porphyrin skeleton (−0.43e to 0.50e) and S[BOND]H bond (−0.55e to 0.52e)

Joint Use of Bonding Evolution Theory and QM/MM Hybrid Method for Understanding the Hydrogen Abstraction Mechanism via Cytochrome P450 Aromatase

Bonding evolution theory (BET), as a combination of the electron localization function (ELF) and Thom’s catastrophe theory (CT), has been coupled with quantum mechanics/molecular mechanics (QM/MM) method in order to study biochemical reaction paths. The evolution of the bond breaking/forming processes and electron pair rearrangements in an inhomogeneous dynamic environment provided by the enzyme has been elucidated. The proposed methodology is applied in an enzymatic system in order to clarify the reaction mechanism for the hydrogen abstraction of the androstenedione (ASD) substrate catalyzed by the cytochrome P450 aromatase enzyme. The use of a QM/MM Hamiltonian allows inclusion of the polarization of the charges derived from the amino acid residues in the wave function, providing a more accurate and realistic description of the chemical process. The hydrogen abstraction step is found to have five different ELF structural stability domains, whereas the C–H breaking and O–H forming bond process rearrangements are taking place in an asynchronous way