Improved production of heme using metabolically engineered Escherichia coli

Heme has recently attracted much attention due to its promising applications in the food and healthcare industries. However, the current titers and productivities of heme produced by recombinant microorganisms are not high enough for a wide range of applications. In this study, the process for the fermentation of the metabolically engineered Escherichia coli HAEM7 strain was optimized for the high‐level production of heme. To improve the production of heme, different carbon sources, iron concentration in the medium, pH control strategies, induction points, and iron content in the feeding solution were examined. Moreover, strategies of increasing cell density, regular iron supplementation, and supply of excess feeding solution were developed to further improve the production of heme. In the optimized fermentation process, the HAEM7 strain produced 1.03 g/L heme with productivity of 21.5 mg/L/h. The fermentation process and strategies reported here will expedite establishing industry‐level production of heme. A fermentation process for microbial production of free heme was optimized in this study. The authors optimized carbon source and the composition (e.g. phosphate, iron, and other trace metals) of medium/feed and also developed multiple strategies, including delayed initiation of pH control, scheduled overfeeding, and periodic supplementation of iron. These strategies collectively increased the cell density, iron availability, and resistance to stresses, enabling production of more than 1 g/L of heme in 48 h.