The mechanism for nitro group formation in the thaxtomin family of natural products is unknown. Genetic and biochemical studies now show the cytochrome P450 TxtE catalyzes this direct and regioselective nitration, using NO and O2 to modify a tryptophan indole ring. Thaxtomin phytotoxins produced by plant-pathogenic Streptomyces species contain a nitro group that is essential for phytotoxicity. The N,N′-dimethyldiketopiperazine core of thaxtomins is assembled from L-phenylalanine and L-4-nitrotryptophan by a nonribosomal peptide synthetase, and nitric oxide synthase–generated NO is incorporated into the nitro group, but the biosynthesis of the nonproteinogenic amino acid L-4-nitrotryptophan is unclear. Here we report that TxtE, a unique cytochrome P450, catalyzes L-tryptophan nitration using NO and O2.

Oxidative cyclizations, exemplified by the biosynthetic assembly of the penicillin nucleus from a tripeptide precursor, are arguably the most synthetically powerful implementation of C–H activation reactions in nature. Here, we show that Rieske oxygenase-like enzymes mediate regio- and stereodivergent oxidative cyclizations to form 10- and 12-membered carbocyclic rings in the key steps of the biosynthesis of the antibiotics streptorubin B and metacycloprodigiosin, respectively. These reactions represent the first examples of oxidative carbocyclizations catalysed by non-haem iron-dependent oxidases and define a novel type of catalytic activity for Rieske enzymes. A better understanding of how these enzymes achieve such remarkable regio- and stereocontrol in the functionalization of unactivated hydrocarbon chains will greatly facilitate the development of selective man-made C–H activation catalysts.

In the search for iron, an essential element in many biochemical processes, microorganisms biosynthesise dedicated chelators, known as siderophores, to sequester iron from their environment and actively transport the siderophore complex into the cell. This process has been implicated in bacterial pathogenesis and exploited through siderophore-antibiotic conjugates as a method for selective antibiotic delivery. Here we review this Trojan-horse approach including design considerations and potential in diagnostics and infection imaging.