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Uncovering the cytochrome P450-catalyzed methylenedioxy bridge formation in streptovaricins biosynthesis

Author

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  • Guo Sun

    (Wuhan University School of Pharmaceutical Sciences)

  • Chaoqun Hu

    (Wuhan University School of Pharmaceutical Sciences)

  • Qing Mei

    (Wuhan University School of Pharmaceutical Sciences)

  • Minghe Luo

    (Wuhan University School of Pharmaceutical Sciences)

  • Xu Chen

    (Wuhan University School of Pharmaceutical Sciences)

  • Zhengyuan Li

    (Wuhan University School of Pharmaceutical Sciences)

  • Yuanzhen Liu

    (Wuhan University School of Pharmaceutical Sciences)

  • Zixin Deng

    (Wuhan University School of Pharmaceutical Sciences)

  • Zhengyu Zhang

    (Wuhan University School of Pharmaceutical Sciences)

  • Yuhui Sun

    (Wuhan University School of Pharmaceutical Sciences)

Abstract

Streptovaricin C is a naphthalenic ansamycin antibiotic structurally similar to rifamycins with potential anti-MRSA bioactivities. However, the formation mechanism of the most fascinating and bioactivity-related methylenedioxy bridge (MDB) moiety in streptovaricins is unclear. Based on genetic and biochemical evidences, we herein clarify that the P450 enzyme StvP2 catalyzes the MDB formation in streptovaricins, with an atypical substrate inhibition kinetics. Furthermore, X-ray crystal structures in complex with substrate and structure-based mutagenesis reveal the intrinsic details of the enzymatic reaction. The mechanism of MDB formation is proposed to be an intramolecular nucleophilic substitution resulting from the hydroxylation by the heme core and the keto-enol tautomerization via a crucial catalytic triad (Asp89-His92-Arg72) in StvP2. In addition, in vitro reconstitution uncovers that C6-O-methylation and C4-O-acetylation of streptovaricins are necessary prerequisites for the MDB formation. This work provides insight for the MDB formation and adds evidence in support of the functional versatility of P450 enzymes.

Suggested Citation

  • Guo Sun & Chaoqun Hu & Qing Mei & Minghe Luo & Xu Chen & Zhengyuan Li & Yuanzhen Liu & Zixin Deng & Zhengyu Zhang & Yuhui Sun, 2020. "Uncovering the cytochrome P450-catalyzed methylenedioxy bridge formation in streptovaricins biosynthesis," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18336-5
    DOI: 10.1038/s41467-020-18336-5
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