Enhanced bioproduction of anticancer precursor vindoline by yeast cell factories

The pharmaceutical industry faces a growing demand and recurrent shortages in many anticancer plant drugs given their extensive use in human chemotherapy. Efficient alternative strategies of supply of these natural products such as bioproduction by microorganisms are needed to ensure stable and massive manufacturing. Here, we developed and optimized yeast cell factories efficiently converting tabersonine to vindoline, a precursor of the major anticancer alkaloids vinblastine and vincristine. First, fine-tuning of heterologous gene copies restrained side metabolites synthesis towards vindoline production. Tabersonine to vindoline bioconversion was further enhanced through a rational medium optimization (pH, composition) and a sequential feeding strategy. Finally, a vindoline titre of 266 mg l(-1) (88% yield) was reached in an optimized fed-batch bioreactor. This precursor-directed synthesis of vindoline thus paves the way towards future industrial bioproduction through the valorization of abundant tabersonine resources.

Automated summary

The pharmaceutical industry is facing increasing demand and recurrent shortages of anticancer plant drugs, prompting the need for efficient alternative strategies such as bioproduction by microorganisms. In this study, yeast cell factories were developed and optimized to efficiently convert tabersonine to vindoline, a precursor to major anticancer alkaloids. Through fine-tuning gene copies and medium optimization, the bioconversion efficiency was significantly improved, resulting in a vindoline titre of 266 mg l(-1) in an optimized fed-batch bioreactor. This precursor-directed synthesis paves the way towards future industrial bioproduction by valorizing abundant tabersonine resources.