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Unveiling Two Consecutive Hydroxylations: Mechanisms of Aromatic Hydroxylations Catalyzed by Flavin‐Dependent Monooxygenases for the Biosynthesis of Actinorhodin and Related Antibiotics
Author(s) -
Hashimoto Makoto,
Taguchi Takaaki,
Ishikawa Kazuki,
Mori Ryuichiro,
Hotta Akari,
Watari Susumu,
Katakawa Kazuaki,
Kumamoto Takuya,
Okamoto Susumu,
Ichinose Koji
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900490
Subject(s) - actinorhodin , monooxygenase , flavin group , polyketide , stereochemistry , streptomyces coelicolor , reductase , cofactor , biosynthesis , cytochrome , chemistry , biochemistry , biology , streptomyces , cytochrome p450 , enzyme , bacteria , genetics
Flavin‐dependent monooxygenases are ubiquitous in living systems and are classified into single‐ or two‐component systems. Actinorhodin, produced by Streptomyces coelicolor , is a representative polycyclic polyketide that is hydroxylated through the action of the two‐component ActVA‐5/ActVB hydroxylase system. These homologous systems are widely distributed in bacteria, but their reaction mechanisms remain unclear. This in vitro investigation has provided chemical proof of two consecutive hydroxylations via hydroxynaphthalene intermediates involved in actinorhodin biosynthesis. The ActVA‐5 oxygenase component catalyzed a stepwise dihydroxylation of the substrate, whereas the ActVB flavin reductase not only supplied a reduced cofactor, but also regulated the quinone–hydroquinone interconversion of an intermediate. Our study provides clues for understanding the general biosynthetic mechanisms of highly functionalized aromatic natural products with structural diversity.