Enhanced bioproduction of anticancer precursor vindoline by yeast cell factories

Autor: Kulagina, Natalja, Guirimand, Grégory, Melin, Céline, Lemos‐Cruz, Pamela, Carqueijeiro, Ines, De Craene, Johan‐Owen, Oudin, Audrey, Heredia, Vladimir, Koudounas, Konstantinos, Unlubayir, Marianne, Lanoue, Arnaud, Imbault, Nadine, St‐Pierre, Benoit, Papon, Nicolas, Clastre, Marc, Giglioli‐Guivarc’h, Nathalie, Marc, Jillian, Besseau, Sébastien, Courdavault, Vincent
Přispěvatelé: Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Microbial Biotechnology
Microbial Biotechnology, Wiley, 2021, ⟨10.1111/1751-7915.13898⟩
Microbial Biotechnology, Vol 14, Iss 6, Pp 2693-2699 (2021)
ISSN: 1751-7915
Popis: Summary 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.
Saccharomyces was engineered for the precursor directed synthesis of vindoline by integrating the Catharanthus roseus vindoline biosynthetic genes into hotspots of the yeast genome. Fine‐tuning of genes copy numbers as well as optimization of culture conditions (medium composition, pH) improved tabersonine to vindoline conversion up to reaching a 266 mg l−1 vindoline production (88% yield).
Databáze: OpenAIRE
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