Publication: Biotransformación bacteriana de esteroides
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2018-08-30
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Universidad Complutense de Madrid
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Abstract
Los compuestos de naturaleza esteroídica constituyen una familia de moléculas de gran relevancia biológica por su abundancia en la naturaleza y su participación en un amplio abanico de funciones celulares y fisiológicas en distintos organismos (Lednicer, 2011; Nelson y Cox, 2012). Desde mediados del siglo XX, se ha incrementado enormemente el número de moléculas esteroideas debido a la síntesis química de un gran número de compuestos xenobióticos con diferentes propiedades farmacológicas. El estudio de las rutas microbianas de degradación de esteroides ha despertado un gran interés en la comunidad científica en las últimas décadas, impulsado por por la abundancia de esteroides naturales y el aumento considerable de contaminantes xenobióticos esteroideos en el medio ambiente (García et al., 2012). Un número considerable de estos estudios se han realizado con Actinobacterias (Actinomicetos) y en particular, con representantes del suborden Corynebacterineae tales como Mycobacterium, Rhodococcus y Gordonia. Estos géneros incluyen bacterias patógenas como por ejemplo Mycobacterium tuberculosis o Rhodococcus equi, y bacterias o saprófitas o patógenas no-estrictas como por ejemplo Mycobacterium smegmatis, Gordonia neofelifaecis y Rhodococcus jostii. Los avances más importantes en este campo se han logrado en el estudio del catabolismo del colesterol, debido en gran medida al papel de esta molécula en la patogénesis de M. tuberculosis. Sin embargo, las actinobacterias normalmente contienen varios clusters génicos implicados en el catabolismo de esteroides, que les confieren la capacidad de mineralizar un amplio rango de esteroides (p. ej., esteroles, ácidos biliares, testosterona, progesterona). La complejidad de las moléculas esteroideas y por consiguiente de sus procesos de degradación, hace que el estudio de estas rutas sea especialmente difícil. Por otro lado, en la industria farmacéutica se han utilizado desde hace décadas biocatalizadores microbianos para facilitar la síntesis de nuevas moléculas esteroideas (Donova y Egorova, 2012). Para este propósito, tradicionalmente se han utilizado en procesos de biotransformación distintos microorganismos aislados del medio ambiente mejorados mediante técnicas convencionales de mutación al azar y selección. Sin embargo, recientemente se ha comenzado a explorar la implementación de aproximaciones de Ingeniería Metabólica y Biología Sintética para el desarrollo de biocatalizadores mejorados a la carta. De esta manera, en los últimos años se ha producido una convergencia de intereses entre el estudio de las rutas de catabolismo de esteroides y el diseño de biocatalizadores a la carta con fines industriales. Esta Tesis Doctoral se encuadra dentro de esta nueva aproximación experimental...
Steroid compounds are a family of molecules of great biological importance due to their abundance in nature and their participation in a wide range of cellular and physiological functions in different organisms (Lednicer, 2011; Nelson and Cox, 2012). Since the mid-twentieth century, the number of steroid molecules has increased considerably due to the chemical synthesis of a large number of xenobiotic compounds with different pharmacological properties. The study of microbial pathways of steroid degradation has aroused great interest in the scientific community in recent decades, driven by the abundance of natural steroids and the considerable increase of xenobiotic steroid contaminants in the environment (García et al., 2012). A considerable number of these studies have been performed with Actinobacteria (Actinomycetes) and in particular, with representatives of the suborder Corynebacterineae such as Mycobacterium, Rhodococcus and Gordonia. These genera include pathogenic bacteria such as Mycobacterium tuberculosis or Rhodococcus equi, and non-strictly pathogenic or saprophyte bacteria such as Mycobacterium smegmatis, Gordonia neofelifaecis and Rhodococcus jostii. The most important advances in this field have been achieved in the study of cholesterol catabolism, largely due to the role of this molecule in the pathogenesis of M. tuberculosis. However, actinobacteria usually contain several gene clusters involved in the steroid catabolism, which confer on them the ability to mineralize a wide range of steroids (e. g., sterols, bile acids, testosterone, progesterone). The complexity of the steroid molecules and consequently of their degradation processes makes the study of these pathways especially difficult. On the other hand, microbial biocatalysts have been used for decades to facilitate the synthesis of new steroid molecules in the pharmaceutical industry (Donova and Egorova, 2012). For this purpose, different environmentally isolated microorganisms improved by means of conventional random mutation and selection techniques have been traditionally used in biotransformation processes. However, it has recently begun to explore the implementation of Metabolic Engineering and Synthetic Biology approaches for the development of improved biocatalysts à la carte. In this way, in recent years there has been a convergence of interests between the study of steroid catabolic pathways and the design of biocatalysts á la carte for industrial purposes. This Doctoral Thesis is part of this new experimental approach...
Steroid compounds are a family of molecules of great biological importance due to their abundance in nature and their participation in a wide range of cellular and physiological functions in different organisms (Lednicer, 2011; Nelson and Cox, 2012). Since the mid-twentieth century, the number of steroid molecules has increased considerably due to the chemical synthesis of a large number of xenobiotic compounds with different pharmacological properties. The study of microbial pathways of steroid degradation has aroused great interest in the scientific community in recent decades, driven by the abundance of natural steroids and the considerable increase of xenobiotic steroid contaminants in the environment (García et al., 2012). A considerable number of these studies have been performed with Actinobacteria (Actinomycetes) and in particular, with representatives of the suborder Corynebacterineae such as Mycobacterium, Rhodococcus and Gordonia. These genera include pathogenic bacteria such as Mycobacterium tuberculosis or Rhodococcus equi, and non-strictly pathogenic or saprophyte bacteria such as Mycobacterium smegmatis, Gordonia neofelifaecis and Rhodococcus jostii. The most important advances in this field have been achieved in the study of cholesterol catabolism, largely due to the role of this molecule in the pathogenesis of M. tuberculosis. However, actinobacteria usually contain several gene clusters involved in the steroid catabolism, which confer on them the ability to mineralize a wide range of steroids (e. g., sterols, bile acids, testosterone, progesterone). The complexity of the steroid molecules and consequently of their degradation processes makes the study of these pathways especially difficult. On the other hand, microbial biocatalysts have been used for decades to facilitate the synthesis of new steroid molecules in the pharmaceutical industry (Donova and Egorova, 2012). For this purpose, different environmentally isolated microorganisms improved by means of conventional random mutation and selection techniques have been traditionally used in biotransformation processes. However, it has recently begun to explore the implementation of Metabolic Engineering and Synthetic Biology approaches for the development of improved biocatalysts à la carte. In this way, in recent years there has been a convergence of interests between the study of steroid catabolic pathways and the design of biocatalysts á la carte for industrial purposes. This Doctoral Thesis is part of this new experimental approach...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 19-06-2017