A designed hybrid pathway for efficient synthesis of D-pantothenate in E. coli

D-Pantothenate (D-PA), a crucial precursor for coenzyme A, is widely used in various industries. Traditional chemical synthesis of D-PA involves toxic inputs, including cyanide, and generates environmental pollution. Total biosynthesis from glucose still has limitation in long reaction time and low titer. To provide a new approach to D-PA, we designed a hybrid pathway. First, we used green chemical method to convert inexpensive glyoxylate and isobutyaldehyde into 2-hydroxy-3-methyl-3-formylbutyric acid (HMFBA). Then we established a biosynthetic pathway to transform HMFBA into D-PA. Specifically, we engineered a malate dehydrogenase to achieve the efficient stereospecific conversion step. Optimization efforts led to a strain producing 116.5 g/L D-PA in 48 h, which is the highest rate and titier reported so far. This new approach offers a potentially economic and high-rate production route of D-PA.