Resumen de Carotenogenesis in haloarchaea: From genetics to biotechnological and biomedical applications
Los carotenoides son pigmentos sintetizados por una gran variedad de seres vivos, incluyendo hongos, algas, plantas y microorganismos. Son conocidos mayormente por sus propiedades antioxidantes, pero presentan otras propiedades potencialmente beneficiosas, tales como actividad inmunomodulatoria o efectos antitumorales. En la actualidad, hay una demanda creciente de productos de origen natural, y la síntesis microbiana de carotenoides se presenta como una alternativa interesante a la actual síntesis química. Las arqueas halófilas, como Haloferax mediterranei, producen el carotenoide bacteriorruberina (BR), cuya estructura a priori le confiere un gran potencial antioxidante.
El objetivo de este trabajo fue, en primer lugar, optimizar la síntesis de BR utilizando a Haloferax mediterranei como biofactoría y, en segundo lugar, explorar aplicaciones biomédicas de dichos extractos carotenoideos.
En una primera fase, a través de un estudio bioinformático, se identificaron los genes implicados en la síntesis de carotenoides en haloarqueas, los cuales están altamente conservados y se propuso una posible ruta de síntesis. A continuación, se exploró la respuesta de Haloferax mediterranei, en términos de síntesis de BR, a un estrés oxidativo generado por peróxido de hidrógeno. Haloferax mediterranei demostró una elevada tolerancia (hasta 25 mM) y se observó un aumento en la producción del carotenoide en respuesta a concentraciones crecientes del oxidante.
Como resultados del proceso de optimización, la combinación de una reducción en la concentración de sales inorgánicas (12.5%(p/v)), junto con una temperatura del 36,5% y elevada disponibilidad de carbono, en forma de glucosa o almidón (2,5% (p/v)), dio lugar a una de las concentraciones de BR más elevadas que se ha registrado en la literatura.
Además, se caracterizó el potencial antioxidante de los extractos obtenidos a través de cuatro técnicas distintas (ensayos de DPPH, FRAP, ABTS y decoloración del ß-caroteno), confirmando la elevada actividad de los extractos ricos en BR. Por otra parte, se detectó que las variaciones en la concentración de carbono en el medio de cultivo modulan la síntesis de carotenoides, alterando la composición de los extractos y sus propiedades.
Por último, la segunda fase de la tesis estuvo enfocada en la búsqueda de aplicaciones biomédicas. Por ese motivo, se determinó que los extractos ricos en BR producidos por Haloferax mediterranei eran capaces de inhibir las enzimas glucosidasa, amilasa y lipasa pancreática con mayor éxito que inhibidores comerciales, lo cual implica que podrían ser de gran utilidad para reducir el pico de glucosa posprandial en pacientes diabéticos; y la absorción de lípidos a nivel intestinal en pacientes con obesidad. Asimismo, en paralelo se evaluó el efecto de los carotenoides de Haloferax mediterranei en líneas celulares representativas de los subtipos de tumores de mama. Los resultados indicaron que el tratamiento tiene un efecto selectivo sobre las líneas celulares tumorales. Los subtipos más afectados son los tumores luminal A y B, aunque las líneas representativas de tumores triple negativo y aquellos con sobreexpresion de HER2 respondieron favorablemente al tratamiento, lo cual es muy prometedor.
En definitiva, la producción de carotenoides por Haloferax mediterranei puede ser optimizada con éxito a través de la modulación de las condiciones de cultivo, y los extractos obtenidos tienen gran potencial en la industria biotecnológica y biomédica.
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