Sustainable biosynthesis of valuable diterpenes in microbes

Diterpenes, or diterpenoids, are the most abundant and diverse subgroup of terpenoids, the largest family of secondary metabolites. Most diterpenes possess broad biological activities including anti-inflammatory, antiviral, anti-tumoral, antimicrobial, anticancer, antifungal, antidiabetic, cardiovascular protective, and phytohormone activities. As such, diterpenes have wide applications in medicine (e.g., the anticancer drug Taxol and the antibiotic pleuromutilin), agriculture (especially as phytohormones such as gibberellins), personal care (e.g., the fragrance sclareol) and food (e.g., steviol glucosides as low-calorie sweeteners) industries. Diterpenes are biosynthesized in a common route with various diterpene synthases and decoration enzymes like cytochrome P450 oxidases, glycosidases, and acyltransferases. Recent advances in DNA sequencing and synthesis, omics analysis, synthetic biology, and metabolic engineering have enabled efficient production of diterpenes in several chassis hosts like Escherichia coli, Saccharomyces cerevisiae, Yarrowia lipolytica, Rhodosporidium toruloides, and Fusarium fujikuroi. This review summarizes the recently discovered diterpenes, their related enzymes and biosynthetic pathways, particularly highlighting the microbial synthesis of high-value diterpenes directly from inexpensive carbon sources (e.g., sugars). The high titers (>4 g/L) achieved mean that some of these endeavors are reaching or close to commercialization. As such, we envisage a bright future in translating microbial synthesis of diterpenes into commercialization.