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

Guo Sun, Chaoqun Hu, Qing Mei, Minghe Luo, Xu Chen, Zhengyuan Li, Yuanzhen Liu, Zixin Deng, Zhengyu Zhang () and Yuhui Sun ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-18336-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18336-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-18336-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().