On January 17th, 2025, Nature Communications (5-Year Impact Factor=16.1) published a research paper entitled ‘Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits’ online from Hailong Wang’s laboratory at State Key Laboratory of Microbial Technology of Shandong University. Prof. Hailong Wang is the corresponding author, and Doctoral Candidate Yan Liu is the first author.

Modular polyketide synthases (mPKSs) are multidomain enzymes in bacteria that synthesize a variety of pharmaceutically important compounds. In this study, to understand the transcriptional and translational characteristics of these large genes, we split the 13-kb busA gene, encoding a 456-kDa three-module PKS for butenyl-spinosyn biosynthesis, into three smaller separately translated genes encoding one PKS module in an operon. Expression of the native and split busA genes in Streptomyces albus revealed that the majority (>93%) of PKS mRNAs were truncated, resulting in a greater abundance of and a higher synthesis rate for the proteins encoded by genes closer to the operon promoter. Splitting the large busA gene rescued translation of truncated mRNAs into functional PKS subunits, and increased the biosynthetic efficiency of butenyl-spinosyn PKS by 13-fold. The truncated mRNA translation rescue strategy was also used to split the 19-kb aveA2 gene which encodes the 666-kDa AveA2 PKS protein for the avermectin biosynthesis, and the 22-kb epoD gene which encodes the 764-kDa EpoD PKS protein for the epothilone biosynthesis. The yield of avermectin and epothilone was increased by 5-fold and 10-fold, respectively. The truncated mRNA translation rescue strategy will facilitate engineering of multi-domain proteins to enhance their functions.

This work was supported by the National Natural Science Foundation of China, National Key Research & Development Program of China, Natural Science Foundation of Shandong Province, and so on.