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Phylogenomics and metabolic engineering reveal a conserved gene cluster in Solanaceae plants for withanolide biosynthesis

Author

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  • Samuel Edward Hakim

    (Leibniz University Hannover
    Leibniz University Hannover)

  • Nancy Choudhary

    (TU Braunschweig
    Kirschallee 1)

  • Karan Malhotra

    (Leibniz University Hannover)

  • Jian Peng

    (Leibniz University Hannover
    Leibniz University Hannover)

  • Arne Bültemeier

    (Leibniz University Hannover
    Leibniz University Hannover)

  • Ahmed Arafa

    (Leibniz University Hannover
    Leibniz University Hannover
    Tanta University)

  • Ronja Friedhoff

    (TU Braunschweig)

  • Maximilian Bauer

    (Leibniz University Hannover)

  • Jessica Eikenberg

    (Leibniz University Hannover
    Leibniz University Hannover)

  • Claus-Peter Witte

    (Leibniz University Hannover)

  • Marco Herde

    (Leibniz University Hannover)

  • Philipp Heretsch

    (Leibniz University Hannover)

  • Boas Pucker

    (TU Braunschweig
    Kirschallee 1)

  • Jakob Franke

    (Leibniz University Hannover
    Leibniz University Hannover)

Abstract

Withanolides are steroidal lactones from nightshade (Solanaceae) plants with untapped drug potential due to limited availability of minor representatives caused by lack of biosynthetic pathway knowledge. Here, we combine phylogenomics with metabolic engineering to overcome this limitation. By sequencing the genome of the medicinal plant ashwagandha (Withania somnifera) and comparing it with nine Solanaceae species, we discover a conserved withanolide biosynthesis gene cluster, consisting of two sub gene clusters with differing expression patterns. We establish metabolic engineering platforms in yeast (Saccharomyces cerevisiae) and the model plant Nicotiana benthamiana to reconstitute the first five oxidations of withanolide biosynthesis, catalysed by the cytochrome P450 monooxygenases CYP87G1, CYP88C7, and CYP749B2 and a short-chain dehydrogenase/reductase, producing the aglycone of withanoside V. Enzyme functions are conserved within both sub gene clusters in W. somnifera and between W. somnifera and Physalis pruinosa. Our work sets the basis for biotechnological withanolide production to unlock their pharmaceutical potential.

Suggested Citation

  • Samuel Edward Hakim & Nancy Choudhary & Karan Malhotra & Jian Peng & Arne Bültemeier & Ahmed Arafa & Ronja Friedhoff & Maximilian Bauer & Jessica Eikenberg & Claus-Peter Witte & Marco Herde & Philipp , 2025. "Phylogenomics and metabolic engineering reveal a conserved gene cluster in Solanaceae plants for withanolide biosynthesis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61686-1
    DOI: 10.1038/s41467-025-61686-1
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    References listed on IDEAS

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