Current Understanding of the Biosynthesis of the Unique Nitrogenase Cofactor Core

Abstract

Nitrogenase catalyzes the remarkable chemical transformations of N2 to NH3, and C1 substrates to hydrocarbons, under ambient conditions. The best-studied Mo-nitrogenase utilizes a complex metallocofactor ([MoFe7 S9 C(R-homocitrate)]) for substrate binding and reduction; however, the complexity of this cofactor has hindered a better understanding of its mechanistic details and chemical synthesis so far. Driven by the pressing questions related to the structure and function of the nitrogenase cofactor, research in the past decades has been focused on unraveling the biosynthetic mechanism of this metallocluster in order to cultivate knowledge of how the cofactor is functionalized in this process. In this review, we summarize the recent advances toward a better understanding of the biosynthesis of the nitrogenase cofactor, with a particular focus on the biosynthetic events related to the generation of its unique core structure. Information derived from these studies has unveiled a novel, radical SAM-dependent mechanism of carbide insertion that orchestrates the coupling and rearrangement of two 4Fe cluster modules into a unique 8Fe cofactor core, as well as a sulfite-based route that incorporates a ‘9th sulfur’ at the catalyti-cally important “belt” region of the cofactor. Continued efforts along this line of investigation will further unravel the biosynthetic mechanism of the nitrogenase cofactor while facilitating investigations into the elusive catalytic mechanism of nitrogenase.