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

Author

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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
    Faculty of Pharmacy, University of Barcelona)

  • Dragana Božić

    (Group of Biotechnology of Pharmaceutical Plants, Laboratory of Pharmacognosy, Aristotle University of Thessaloniki
    Present address: Institute for Biological Research ‘Siniša Stanković’, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia)

  • 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
    Faculty of Pharmacy, University of Barcelona)

  • Alain Tissier

    (Leibniz Institute of Plant Biochemistry)

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.

Suggested Citation

  • Ulschan Scheler & Wolfgang Brandt & Andrea Porzel & Kathleen Rothe & David Manzano & Dragana Božić & Dimitra Papaefthimiou & Gerd Ulrich Balcke & Anja Henning & Swanhild Lohse & Sylvestre Marillonnet , 2016. "Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast," Nature Communications, Nature, vol. 7(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12942
    DOI: 10.1038/ncomms12942
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    Cited by:

    1. Yifeng Zhang & Jie Gao & Lin Ma & Lichan Tu & Tianyuan Hu & Xiaoyi Wu & Ping Su & Yujun Zhao & Yuan Liu & Dan Li & Jiawei Zhou & Yan Yin & Yuru Tong & Huan Zhao & Yun Lu & Jiadian Wang & Wei Gao & Luq, 2023. "Tandemly duplicated CYP82Ds catalyze 14-hydroxylation in triptolide biosynthesis and precursor production in Saccharomyces cerevisiae," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Jiadong Hu & Shi Qiu & Feiyan Wang & Qing Li & Chun-Lei Xiang & Peng Di & Ziding Wu & Rui Jiang & Jinxing Li & Zhen Zeng & Jing Wang & Xingxing Wang & Yuchen Zhang & Shiyuan Fang & Yuqi Qiao & Jie Din, 2023. "Functional divergence of CYP76AKs shapes the chemodiversity of abietane-type diterpenoids in genus Salvia," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Abigail E. Bryson & Emily R. Lanier & Kin H. Lau & John P. Hamilton & Brieanne Vaillancourt & Davis Mathieu & Alan E. Yocca & Garret P. Miller & Patrick P. Edger & C. Robin Buell & Björn Hamberger, 2023. "Uncovering a miltiradiene biosynthetic gene cluster in the Lamiaceae reveals a dynamic evolutionary trajectory," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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