Publication: Producción de esteroides mediante ingeniería de citocromos
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2017-05-19
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Universidad Complutense de Madrid
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Abstract
"Introducción" La producción de esteroides resulta de gran interés para el sector farmacéutico debido al amplio rango de actividades terapéuticas que poseen estas moléculas, que han sido utilizadas para tratar y prevenir enfermedades en distintos campos clínicos tan relevantes como los de la endocrinología, la oncología, la reumatología o la ginecología entre otros. Actualmente, estos compuestos se producen por síntesis química o mediante su combinación con procesos de biotransformación microbiológicos, presentando estos últimos interesantes ventajas pero también algunos inconvenientes que han de ser reducidos. Los biocatalizadores empleados en las biotransformaciones son bacterias y hongos capaces de realizar las modificaciones químicas oportunas en estas moléculas dando lugar al compuesto de interés. Pero también pueden realizar modificaciones colaterales dando lugar a otros subproductos que hacen descender los rendimientos de producción. En general estas biotransformaciones se realizan partiendo de sintonas previamente sintetizadas o de materias primas de bajo coste como el colesterol o los fitosteroles. A pesar del enorme conocimiento actual en las tecnologías de ingeniería genética y metabólica, apenas se han realizado aportaciones en este sentido para la mejora genética de los biocatalizadores empleados en la industria de los esteroides. Esto es en parte comprensible, ya que realizar mejoras genéticas dirigidas en estos microorganismos es complicado. Por ello el desarrollo de nuevos procesos de producción de compuestos esteroideos de interés farmacológico e industrial utilizando biocatalizadores modificados mediante técnicas de ingeniería genética ha sido el objetivo principal de esta Tesis Doctoral. "Objetivos" Teniendo en cuenta la relevancia de la producción de los esteroides por biotransformación y asumiendo que los microorganismos empleados como biocatalizadores hasta la fecha están poco optimizados, resulta de gran interés la posibilidad de aplicar las modernas tecnologías de la ingeniería metabólica y la biología sintética para obtener microorganismos más eficientes que los actuales. Por este motivo el trabajo realizado en esta Tesis Doctoral se ha centrado en la mejora de la producción de esteroides 11α- y 11β-hidroxilados farmacológicamente activos...
"Introduction" The production of steroids is a very important target for the pharmaceutical sector because of the broad range of their therapeutic activities and their use to cure and prevent some kind of diseases in the important fields of endocrinology, oncology, rheumatology, gynaecology and others. Nowadays, these compounds are produced using a chemical approach or by its combination with microbiological biotransformations. Although this biotechnological approach has several advantages it has still some disadvantages that remain to be solved. Bacteria and specially fungi are used as biofactories to perform the biotransformations and deliver the products of interest, but these organisms might perform other modifications leading to undesired by-products, causing a dramatic reduction of production yields. Currently, synthetic synthons or low cost raw materials, such as cholesterol or phytosterols are used as a substrate for these biotransformations. Despite of the great knowledge acquired during the last 30 years on metabolic engineering of bacteria and fungi, it is surprising the few advances produced in the genetic improvement of steroid biocatalysts. This fact could be explained because performing à la carte genetic improvements in this kind of microorganisms is complicate in general. Taking into account these premises, the development of steroid production processes using improved biocatalysts by genetic and metabolic engineering tools has been the major goal of this Doctoral Thesis. "Objectives" In accordance to the importance of the steroid production for the pharmaceutical sector and assuming that no (or little) genetically optimized biofactories are used in the industry nowadays, we consider a crucial objective to explore the use of the metabolic and synthetic engineering technologies in order to obtain more efficient biofactories for these purposes. In this Thesis we have focused our aim on the production of pharmacologically active11α/β-hydroxylated steroids. In order to obtain this main goal, we defined the followed objectives: 1. Production of 11α-hydroxylated steroids of pharmaceutical and industrial interest from synthons and low cost raw materials such as cholesterol and phytosterols. 2. Production of 11β-hydroxylated steroids of pharmaceutical and industrial interest from synthons and low cost raw materials such as cholesterol and phytosterols...(residuo del biodiesel)” profundiza en la revalorización biotecnológica del residuo para producir un compuesto de mayor valor añadido, el 2,3-butanodiol. Hasta el momento, este bioproceso ha sido escasamente estudiado, hecho que pone de manifiesto la justificación de esta investigación. La metodología empleada para el desarrollo del bioproceso comprende diferentes etapas, descritas a continuación...
"Introduction" The production of steroids is a very important target for the pharmaceutical sector because of the broad range of their therapeutic activities and their use to cure and prevent some kind of diseases in the important fields of endocrinology, oncology, rheumatology, gynaecology and others. Nowadays, these compounds are produced using a chemical approach or by its combination with microbiological biotransformations. Although this biotechnological approach has several advantages it has still some disadvantages that remain to be solved. Bacteria and specially fungi are used as biofactories to perform the biotransformations and deliver the products of interest, but these organisms might perform other modifications leading to undesired by-products, causing a dramatic reduction of production yields. Currently, synthetic synthons or low cost raw materials, such as cholesterol or phytosterols are used as a substrate for these biotransformations. Despite of the great knowledge acquired during the last 30 years on metabolic engineering of bacteria and fungi, it is surprising the few advances produced in the genetic improvement of steroid biocatalysts. This fact could be explained because performing à la carte genetic improvements in this kind of microorganisms is complicate in general. Taking into account these premises, the development of steroid production processes using improved biocatalysts by genetic and metabolic engineering tools has been the major goal of this Doctoral Thesis. "Objectives" In accordance to the importance of the steroid production for the pharmaceutical sector and assuming that no (or little) genetically optimized biofactories are used in the industry nowadays, we consider a crucial objective to explore the use of the metabolic and synthetic engineering technologies in order to obtain more efficient biofactories for these purposes. In this Thesis we have focused our aim on the production of pharmacologically active11α/β-hydroxylated steroids. In order to obtain this main goal, we defined the followed objectives: 1. Production of 11α-hydroxylated steroids of pharmaceutical and industrial interest from synthons and low cost raw materials such as cholesterol and phytosterols. 2. Production of 11β-hydroxylated steroids of pharmaceutical and industrial interest from synthons and low cost raw materials such as cholesterol and phytosterols...(residuo del biodiesel)” profundiza en la revalorización biotecnológica del residuo para producir un compuesto de mayor valor añadido, el 2,3-butanodiol. Hasta el momento, este bioproceso ha sido escasamente estudiado, hecho que pone de manifiesto la justificación de esta investigación. La metodología empleada para el desarrollo del bioproceso comprende diferentes etapas, descritas a continuación...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular I, leída el 12-07-2016