Controlling the feed rate of glucose and propanol for the enhancement of erythromycin production and exploration of propanol metabolism fate by quantitative metabolic flux analysis

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In this paper, several different fermentation experiments were designed to address whether modulating glucose and propanol feeds could benefit the production level of erythromycin during pilot plant (30 L) fermentation. Results showed that glucose feed rate (determined by a set high or low culture pH) had no effect on erythromycin production, indicating that glucose was not the limiting factor for erythromycin biosynthesis under these conditions. It was found that decreasing glucose feed could stimulate the consumption of propanol, and the high erythromycin production (12.49 ± 0.50 mg ml⁻¹) was achieved by controlling the feed rates of glucose and propanol. The quantitative metabolic flux analysis disclosed that high propanol consumption increased the pool size of propionyl-CoA (~2.147 mmol g⁻¹ day⁻¹) and methylmalonyl-CoA (~1.708 mmol g⁻¹ day⁻¹). It was also found that 45-77 % of the propanol went into the TCA cycle which strengthened the conclusion that blocking the propionate pathway to TCA cycle could lead to a significant increase in erythromycin production in carbohydrate-based media (Reeves et al. Ind Microbiol Biotechnol 7:600-609, 2006). In addition, the results also suggested that a relative low intracellular ATP level resulting from low glucose feed did not limit the erythromycin biosynthesis, and a relatively high NADPH should be beneficial for erythromycin biosynthesis.