Substrate Controlled Fed‐Batch Production of l‐Lysine with Corynebacterium glutamicum

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Abstract
A fed‐batch process for the production of l‐lysine with Corynebacterium glutamicum in a stirred tank reactor was developed up to a 150‐L scale applying the general approach of reaction engineering: Experimental optimization of medium composition (13 components: mineral salts and biotin) in parallel shake‐flask experiments using a Genetic Algorithm and the study of l‐leucine, ammonia, and phosphate supply in glucose controlled fed‐batch fermentations resulted in a volumetric l‐lysine productivity of 8.3 mol/(m3·h), a l‐lysine yield of 32% (mol/mol), and a l‐lysine concentration of 500 mM. The glucose concentration was controlled to 50 mM using on‐line HPLC and semicontinuous extended Kalman‐filter with a minimum variance controller. Nitrogen accumulation of the C. glutamicum cells in the early process phase for subsequent l‐lysine formation was identified by means of a reaction engineering analysis. Glucose limitation in the inoculum (1–2 h) results in growth linked l‐lysine production with a differential l‐lysine selectivity of 38% (mol/mol) and a maximum cell specific l‐lysine production rate of 1.1 mmol/(g·h) . l‐Lysine was not growth linked produced, if the inoculum was transferred at the exponential state.