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Production de succinate par Corynebacterium glutamicum en microaérobiose : approches expérimentales et numériques, de l’échelle métabolique au bioréacteur

Abstract : Succinate is a diacid used nowadays as a building block in the synthesis of various molecules of interest. It is mostly produced by chemical synthesis. A part of succinate is industrially produced using a microbiological process. Corynebacterium glutamicum, a well-known industrial producer of amino acids, is able to produce organic acids, in particular succinate, under micro-aerobic and anaerobic conditions. The aim of this work was thus to understand the physiological response of C. glutamicum 2262 to change in oxygen supply conditions. Both experimental and numerical tools have been implemented. The first step was to identify, experimentally, the parameters influencing the physiological response of C. glutamicum 2262 during batch and continuous cultures. This approach allowed to identify oxygenation level and residual glucose concentration as key parameters for organic acids production. The ratio OUR/GUR was also defined as a relevant indicator of the physiological state of C. glutamicum 2262. It was observed that organic acids were simultaneously produced during micro-aerobic phase corresponding to ratio below 1, whereas, above this value, a maximal growth was obtained. The maximal succinate production was obtained at the lower oxygenation level. Moreover, a re-consumption of the produced succinate was also observed when a threshold residual concentration of glucose was reached. Considering the influence of these two key parameters, a highly performant fed-batch process for the succinate production using a wild-type strain of C. glutamicum was defined. Then, a kinetic model was developed. This primary model was then generalized by integrating a correlation between kinetic parameters of model and oxygenation level. The results of both primary and generalized model simulation, showed an excellent agreement with the experimental data. The generalized model was then successfully transposed to a C. glutamicum mutant strain. In addition, a simplified metabolic model for C. glutamicum 2262 was constructed to understand the metabolic response of this bacterium in micro-aerobiosis. Both predicted production fluxes of lactate in microaerobiosis and of biomass synthesis during aerobiosis phase, under stationary conditions, agreed with the experimental data. This metabolic model was also able to predict, under dynamic conditions, the concentration profiles of the succinate during highly limited oxygen supply conditions.
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Submitted on : Wednesday, January 12, 2022 - 11:47:10 AM
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Amani Briki. Production de succinate par Corynebacterium glutamicum en microaérobiose : approches expérimentales et numériques, de l’échelle métabolique au bioréacteur. Génie des procédés. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0082⟩. ⟨tel-03354975⟩

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