Structured Model‐Based Analysis and Control of the Hyaluronic Acid Fermentation by Streptococcuszooepidemicus: Physiological Implications of Glucose and Complex‐Nitrogen‐Limited Growth

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Abstract
The hyaluronic acid (HA) fermentation by Streptococcus zooepidemicus under anaerobic and aerated conditions in glucose-complex media was well described by a structured, two-compartment model. The two-compartment model framework was found to be robust, easily adaptable, and able to predict the transient consumption of substrates and formation of products. Aerobic culture produced a substantially higher concentration of HA than an equivalent anaerobic culture; however biomass-specific growth rate and yield were lower due to partial inhibition by hydrogen peroxide. The model was then used to investigate the physiological implications of glucose and complex-nitrogen-limited growth on the anaerobic production of hyaluronic acid (HA). Glucose-limited growth agreed well with model predictions, although the HA molecular weight was lower than expected even though the absolute HA concentration remained unaffected. Heterofermentative growth was also observed for growth rates below 0.1 h(-)(1). Despite a comparatively lower specific growth rate, the biomass yield was higher; however the metabolic shift did not significantly affect HA production. For complex-nitrogen-limited growth, diauxic growth on complex-nitrogen (yeast extract) was observed and explained by partitioning the array of nitrogen components into two distinct but homogeneous pools. While nitrogen-limited growth was found to increase the HA to biomass yield, like that observed under glucose-limited growth, the resulting HA molecular weight was reduced.