Activation of PrimaryC–H Bonds in OxidativeCyclizations of Tambjamines Catalyzed by Rieske Oxygenases TamC and <i>Pt</i>TamC

Tambjamines are complex bipyrrole-containing natural products that possess promising bioactive properties. Although <i>Pseudoalteromonas citrea</i> is known to produce both cyclic tambjamine MYP1 and the linear precursor (YP1), the biosynthetic machinery used to catalyze the site-selective oxidative carbocyclization at the unactivated 1° carbon of YP1 has remained unclear. Here, we demonstrate that a three-component Rieske system consisting of an oxygenase (TamC) and two redox partner proteins is responsible for this unprecedented activity on YP1 and potentially, a non-native substrate (BE-18591). We also show that a homologous oxidase from <i>Pseudoalteromonas tunicata</i> (<i>Pt</i>TamC) can function together with the partner proteins from <i>P. citrea</i> to process both YP1 and BE-18591. These reactions represent the first Rieske oxygenase-catalyzed activations of C–H bonds at 1° carbons, resulting in carbon–carbon bond formation. The use of TamC and <i>Pt</i>TamC to potentially generate the new-to-nature cyclic analogue of BE-18591 suggests the enormous biocatalytic potential of these Rieske systems to facilitate late-stage oxidative cyclizations at terminal C(sp3)–H bonds.