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Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast

Ulschan Scheler, Wolfgang Brandt, Andrea Porzel, Kathleen Rothe, David Manzano, Dragana Božić, Dimitra Papaefthimiou, Gerd Ulrich Balcke, Anja Henning, Swanhild Lohse, Sylvestre Marillonnet, Angelos K. Kanellis, Albert Ferrer and Alain Tissier ()
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Ulschan Scheler: Leibniz Institute of Plant Biochemistry
Wolfgang Brandt: Leibniz Institute of Plant Biochemistry
Andrea Porzel: Leibniz Institute of Plant Biochemistry
Kathleen Rothe: Leibniz Institute of Plant Biochemistry
David Manzano: Program of Plant Metabolism and Metabolic Engineering, Centre for Research in Agricultural Genomics
Dragana Božić: Group of Biotechnology of Pharmaceutical Plants, Laboratory of Pharmacognosy, Aristotle University of Thessaloniki
Dimitra Papaefthimiou: Group of Biotechnology of Pharmaceutical Plants, Laboratory of Pharmacognosy, Aristotle University of Thessaloniki
Gerd Ulrich Balcke: Leibniz Institute of Plant Biochemistry
Anja Henning: Leibniz Institute of Plant Biochemistry
Swanhild Lohse: Leibniz Institute of Plant Biochemistry
Sylvestre Marillonnet: Leibniz Institute of Plant Biochemistry
Angelos K. Kanellis: Group of Biotechnology of Pharmaceutical Plants, Laboratory of Pharmacognosy, Aristotle University of Thessaloniki
Albert Ferrer: Program of Plant Metabolism and Metabolic Engineering, Centre for Research in Agricultural Genomics
Alain Tissier: Leibniz Institute of Plant Biochemistry

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12942

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