Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast
Ulschan Scheler, Wolfgang Brandt, Andrea Porzel, Kathleen Rothe, David Manzano, Dragana Bozic, Dimitra Papaefthimiou, Gerd Ulrich Balcke, Anja Henning, Swanhild Lohse, Sylvestre Marillonnet, Angelos K. Kanellis, Albert Ferrer,* and Alain Tissier
*Departament de Bioquímica i Fisiologia (Secció de Bioquímica i Biologia Molecular)
Abstract: Rosemary extracts containing the phenolic diterpenes carnosic acid and its derivative carnosol are approved food additives used in an increasingly wide range of products to enhance shelf-life, thanks to their high anti-oxidant activity. We describe here the elucidation of the complete biosynthetic pathway of carnosic acid and its reconstitution in yeast cells. Cytochrome P450 oxygenases (CYP76AH22-24) from Rosmarinus officinalis and Salvia fruticosa
already characterized as ferruginol synthases are also able to produce 11-hydroxyferruginol. Modelling-based mutagenesis of three amino acids in the related ferruginol synthase (CYP76AH1) from S. miltiorrhiza is sufficient to convert it to a 11-hydroxyferruginol synthase (HFS). The three sequential C20 oxidations for the conversion of 11-hydroxyferruginol to carnosic acid are catalysed by the related CYP76AK6-8. The availability of the genes for the biosynthesis of carnosic acid opens opportunities for the metabolic engineering
of phenolic diterpenes, a class of compounds with potent anti-oxidant, anti-inflammatory and anti-tumour activities.
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