Chapter 12: Oxygenases, Thwarted Oxygenases, and Oxygen-dependent Halogenases

Oxygenases, both flavin-dependent and iron-dependent, act on all classes of natural products, often late in scaffold maturation, to introduce oxygen functional groups, including hydroxyl and epoxide groups. The hydroxyl groups then function as nucleophiles for alkylations, acylations, and glycosylations. The epoxides function as electrophiles in a variety of ring-opening and scaffold rearrangements, as in oxidosqualene cyclizations to sterols. Three variants of iron-containing oxygenases are heme iron (cytochrome P450)-based, nonheme mononuclear iron-based, and di-iron catalysts, all proceeding via high-valent iron-oxo oxidants and radical pathways in cosubstrate oxygen transfers. A substantial fraction of all three types of iron oxygenases act as thwarted oxygenases: the triplet O₂ substrate is required to create the high-valent iron-oxo and attendant cosubstrate radical species, but oxygenation half-reactions are not completed. Instead, the cosubstrate radicals react internally and O₂ is ultimately reduced to two molecules of H₂O. These include penicillin and cephalosporin synthases, three P450s that crosslink the vancomycin heptapeptide backbone, okaramine biogenesis, reticuline to salutaridine in morphine biosynthesis, pinoresinol formation in plant phenylpropanoid pathways, and rebeccamycin and staurosporine indolocarbazole assembly. A third subgrouping of oxygen-consuming enzymes are O₂-dependent halogenases. Flavin-dependent halogenases generate HOCl equivalents as sources of [Cl⁺] ions to electron-rich nucleophiles, while iron-dependent halogenases transfer [Cl<o>˙] equivalents from iron oxychloride complexes, rather than [˙OH] equivalents, to cosubstrate radicals.