Biological nitrogen fixation — the reduction of N2 to two NH3 molecules — is catalyzed by the enzyme nitrogenase. N2 binds to the active-site multi-metallic cluster in the nitrogenase MoFe protein, the FeMo-cofactor ([7Fe-9S-Mo-homocitrate-C]; FeMo-co), and is reduced only after the MoFe protein has accumulated four electrons/protons. This raises the fundamental question, how can a cluster progressively accumulate four reducing equivalents, given that they are delivered one-at-a-time from a protein with a fixed and only modestly low reduction potential? As a followup question, what is the process by these equivalents activate FeMo-co to bind and reduce the extremely stable N2 molecule. But perhaps the greatest mystery of nitrogenase function has been, why does the enzyme exhibit a limiting stoichiometry that requires eight reducing equivalents not the six required chemically, N2 + 8e- +16ATP + 8H+ → 2NH3 + H2 + 16ADP + 16Pi a stoichiometry that incorporates obligatory generation of H2 upon N2 binding. As the delivery of each electron requires the hydrolysis of two MgATP, the formation of H2 thus apparently ‘wastes’ 25% of the total energy supplied by the hydrolysis of ATP. We have discovered connections among such questions, and proposed the answers to these and others, through enzymological and advanced paramagnetic resonance studies of intermediates formed with nitrogenous substrates, in combination with fundamental considerations of the redox properties and catalytic reactivity of metal clusters. These answers are grounded in the ‘hydride chemistry’ of FeMo-co, and rely strongly on parallel studies with the alternate substrate, C2H2, and on the organometallic chemistry of alkynes and alkenes, as well as on spectroscopic studies of inorganic biomimetic complexes.

Inorganic chemistry of biological nitrogen fixation

249th National Meeting (2015)

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