Artificial Biosynthetic Pathway for an Unnatural Terpenoid with an Iridiumcontaining P450

Synthetic biology enables microbial hosts to produce complex molecules that areotherwise produced by organisms that are rare or difficult to cultivate, but the structures of thesemolecules are limited to chemical reactions catalyzed by natural enzymes. The integration ofartificial metalloenzymes (ArMs) that catalyze abiotic reactions into metabolic networks couldbroaden the cache of molecules produced biosynthetically by microorgansms. We report theassembly of an ArM containing an iridium-porphyrin complex in the cytoplasm of a terpeneproducing Escherichia coli by a heterologous heme transport machinery, and insertion of this ArMinto a natural biosynthetic pathway to produce an unnatural terpenoid. This work shows thatsynthetic biology and synthetic chemistry, incorporated together in whole cells, can producemolecules previously inaccessible to nature.