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.

Cytokinin-mediated leaf manipulation by a leafminer caterpillar.

A large number of hypotheses have been proposed to explain the adaptive significance and evolution of the endophagous-feeding mode, nutritional benefits being considered to be one of the main advantages. Leaf-mining insects should feed on most nutritional tissues and avoid tissues with high structural and/or biochemical plant defences. This selective feeding behaviour could furthermore be reinforced by manipulating the plant physiology, as suggested by the autumnal formation of 'green islands' around mining caterpillars in yellow leaves. The question we address here is how such metabolic manipulation occurs and what the nutritional consequences for the insect are. We report a large accumulation of cytokinins in the mined tissues which is responsible for the preservation of functional nutrient-rich green tissues at a time when leaves are otherwise turning yellow. The analogy with other plant manipulating organisms, in particular galling insects, is striking.