Structural Basis for the Prenylation Reaction of Carbazole‐Containing Natural Products Catalyzed by Squalene Synthase‐Like Enzymes

Some enzymes annotated as squalene synthase catalyze the prenylation of carbazole‐3,4‐quinone‐containing substrates in bacterial secondary metabolism. Their reaction mechanisms remain unclear because of their low sequence similarity to well‐characterized aromatic substrate prenyltransferases (PTs)....

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Published in:Angewandte Chemie International Edition 2022-05, Vol.61 (20), p.e202117430-n/a
Main Authors: Nagata, Ryuhei, Suemune, Hironori, Kobayashi, Masaya, Shinada, Tetsuro, Shin‐ya, Kazuo, Nishiyama, Makoto, Hino, Tomoya, Sato, Yusuke, Kuzuyama, Tomohisa, Nagano, Shingo
Format: Article
Language:English
Subjects:
Biological Products
Biosynthesis
Carbazole
Carbazoles
Catalysis
Crystal structure
Dimethylallyltranstransferase - metabolism
Enzymes
Farnesyl-Diphosphate Farnesyltransferase - metabolism
Hydrophobicity
Metabolism
Natural products
Prenylation
Prenyltransferase
Prenyltransferases
Quinones
Reaction mechanisms
Squalene
Streptomyces
Structural Biology
Substrate Specificity
Substrates
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Summary:Some enzymes annotated as squalene synthase catalyze the prenylation of carbazole‐3,4‐quinone‐containing substrates in bacterial secondary metabolism. Their reaction mechanisms remain unclear because of their low sequence similarity to well‐characterized aromatic substrate prenyltransferases (PTs). We determined the crystal structures of the carbazole PTs, and these revealed that the overall structure is well superposed on those of squalene synthases. In contrast, the stacking interaction between the prenyl donor and acceptor substrates resembles those observed in aromatic substrate PTs. Structural and mutational analyses suggest that the Ile and Asp residues are essential for the hydrophobic and hydrophilic interactions with the carbazole‐3,4‐quinone moiety of the prenyl acceptor, respectively, and a deprotonation mechanism of an intermediary σ‐complex involving a catalytic triad is proposed. Our results provide a structural basis for a new subclass of aromatic substrate PTs. Carbazole prenyltransferase was found to combine the overall structure of squalene synthase and the elegant stacking interaction between prenyl diphosphate and aromatic compounds observed in the aromatic substrate prenyltransferase. Structural and mutational analyses revealed the binding and deprotonation mechanisms of the carbazole‐3,4‐quinone moiety of the prenyl acceptor.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202117430