Activation of Primary C-H Bonds in Oxidative Cyclizations of Tambjamines Catalyzed by Rieske Oxygenases TamC and PtTamC

Tambjamines are complex bipyrrole-containing natural prod-ucts that possess promising bioactive properties. Although Pseudoalteromonas citrea 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 re-mained 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 a non-native substrate (BE-18591). We also show that a homologous oxidase from Pseudoalteromonas tunicata (PtTamC) can function together with the partner proteins from P. citrea to process both YP1 and BE-18591. These reactions represent the first Rieske oxygenase-catalyzed activations of C-H bonds at 1° carbons. The use of TamC and PtTamC to generate the new-to-Nature cyclic analogue of BE-18591 illustrates the enormous biocatalytic potential of these Rieske systems to facilitate late-stage oxidative cyclizations at terminal C(sp3)-H bonds.