Nitrogenase - Where Haber-Bosch meets Fischer-Tropsch

Nitrogenase catalyzes the reduction of atmospheric dinitrogen to bioavailable ammonia, a process that supports the existence of the entire human population. Additionally, nitrogenase reduces carbon monoxide to hydrocarbons, highlighting its potential for coupling environmental health with sustainable energy production. Unlike industrial Haber-Bosch (ammonia synthesis) and Fischer-Tropsch (carbon fuel synthesis) processes, nitrogenase operates at ambient conditions with protons and electrons as reducing agents, making it an attractive model for chemical energy conversion. Our long-term vision is to advance the mechanistic understanding of nitrogenase assembly and reactivity while leveraging its unique properties for innovative, environmental sustainability applications. In the next five years, we propose to use combined genetic, biochemical, spectroscopic and structural approaches to investigate how M-cluster, the unique metallocofactor of the molybdenum nitrogenase, is assembled into a functional unit, with a focus on the radical SAM-dependent carbide insertion concomitant the formation of an 8Fe cofactor core, the in vivo source and insertion mechanism of the ‘9th sulfur’. and the mobilization of Mo for cofactor maturation. Through our proposed studies, we expect to further refine the biosynthetic pathway of the unique metallocofactor of nitrogenase, which will provide crucial insights into the structural-functional relationship of this important enzyme and reveal general principles of the assembly mechanisms of complex metalloclusters in biological systems. Additionally, we will explore the reactivity of the vanadium nitrogenase, notable for surpassing its molybdenum counterpart in its capacity to reduce carbon monoxide to hydrocarbons. This unique trait of vanadium nitrogenase makes it a valuable tool for carbon recycling. In the next 5 years, we will use hybrid systems of vanadium nitrogenase to dissect its reactivity toward carbon monoxide by accumulating intermediates through modulation of electron flux (via heterometal variation), proton flux (via organic compound alteration), and electron availability (via mismatched electron donors). Through our proposed studies, we expect to identify novel strategies that can also be applied to the mechanistic investigations of enzymatic dinitrogen reduction, as well as establish prototype systems for developing nitrogenase-based applications that recycle carbon wastes into useful chemical products. Project Number: 1R35GM161209-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Markus Ribbe | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $487,953 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - E Study Section[MRAE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11258206