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Bifunctional CYP81AA proteins catalyse identical hydroxylations but alternative regioselective phenol couplings in plant xanthone biosynthesis

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  • Islam El-Awaad

    (Institute of Pharmaceutical Biology, Technische Universität Braunschweig
    Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig
    Present address: Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.)

  • Marco Bocola

    (Institute of Biotechnology, RWTH Aachen University)

  • Till Beuerle

    (Institute of Pharmaceutical Biology, Technische Universität Braunschweig
    Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig)

  • Benye Liu

    (Institute of Pharmaceutical Biology, Technische Universität Braunschweig
    Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig)

  • Ludger Beerhues

    (Institute of Pharmaceutical Biology, Technische Universität Braunschweig
    Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig)

Abstract

Xanthones are natural products present in plants and microorganisms. In plants, their biosynthesis starts with regioselective cyclization of 2,3′,4,6-tetrahydroxybenzophenone to either 1,3,5- or 1,3,7-trihydroxyxanthones, catalysed by cytochrome P450 (CYP) enzymes. Here we isolate and express CYP81AA-coding sequences from Hypericum calycinum and H. perforatum in yeast. Microsomes catalyse two consecutive reactions, that is, 3′-hydroxylation of 2,4,6-trihydroxybenzophenone and C–O phenol coupling of the resulting 2,3′,4,6-tetrahydroxybenzophenone. Relative to the inserted 3′-hydroxyl, the orthologues Hc/HpCYP81AA1 cyclize via the para position to form 1,3,7-trihydroxyxanthone, whereas the paralogue HpCYP81AA2 directs cyclization to the ortho position, yielding the isomeric 1,3,5-trihydroxyxanthone. Homology modelling and reciprocal mutagenesis reveal the impact of S375, L378 and A483 on controlling the regioselectivity of HpCYP81AA2, which is converted into HpCYP81AA1 by sextuple mutation. However, the reciprocal mutations in HpCYP81AA1 barely affect its regiospecificity. Product docking rationalizes the alternative C–O phenol coupling reactions. Our results help understand the machinery of bifunctional CYPs.

Suggested Citation

  • Islam El-Awaad & Marco Bocola & Till Beuerle & Benye Liu & Ludger Beerhues, 2016. "Bifunctional CYP81AA proteins catalyse identical hydroxylations but alternative regioselective phenol couplings in plant xanthone biosynthesis," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11472
    DOI: 10.1038/ncomms11472
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    Cited by:

    1. Chunfang Yang & Liping Zhang & Wenjun Zhang & Chunshuai Huang & Yiguang Zhu & Xiaodong Jiang & Wei Liu & Mengran Zhao & Bidhan Chandra De & Changsheng Zhang, 2022. "Biochemical and structural insights of multifunctional flavin-dependent monooxygenase FlsO1-catalyzed unexpected xanthone formation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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