Total biosynthesis of hydrocortisone from a simple carbon source in yeast - CNRS - Centre national de la recherche scientifique
Article Dans Une Revue Nature Biotechnology Année : 2003

Total biosynthesis of hydrocortisone from a simple carbon source in yeast

Florence Ménard-Szczebara
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David Balbuena
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Jacques Winter
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Roberto Spagnoli
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Denis Pompon
Bruno Dumas
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Résumé

We report on the production of hydrocortisone, the major adrenal glucocorticoid of mammals and an important intermediate of steroidal drug synthesis, from a simple carbon source by recombinant Saccharomyces cerevisiae strains. An artificial and fully self-sufficient biosynthetic pathway involving 13 engineered genes was assembled and expressed in a single yeast strain. Endogenous sterol biosynthesis was rerouted to produce compatible sterols to serve as substrates for the heterologous part of the pathway. Biosynthesis involves eight mammalian proteins (mature forms of CYP11A1, adrenodoxin (ADX), and adrenodoxin reductase (ADR); mitochondrial forms of ADX and CYP11B1; 3β-HSD, CYP17A1, and CYP21A1). Optimization involved modulating the two mitochondrial systems and disrupting of unwanted side reactions associated with ATF2, GCY1, and YPR1 gene products. Hydrocortisone was the major steroid produced. This work demonstrates the feasibility of transfering a complex biosynthetic pathway from higher eukaryotes into microorganisms.

Domaines

Pharmacologie
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Dates et versions

hal-04859712 , version 1 (30-12-2024)

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Citer

Florence Ménard-Szczebara, Cathy Chandelier, Coralie Villeret, Amélie Heneman-Masurel, Stéphane Bourot, et al.. Total biosynthesis of hydrocortisone from a simple carbon source in yeast. Nature Biotechnology, 2003, 21, pp.143-149. ⟨10.1038/nbt775⟩. ⟨hal-04859712⟩
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