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Issue 4, 2019
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How feasible is the reversible S-dissociation mechanism for the activation of FeMo-co, the catalytic site of nitrogenase?

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Abstract

The active site of the enzyme nitrogenase (N2 → NH3) is a Fe7MoS9C cluster that contains three doubly-bridging μ-S atoms around a central belt. A vanadium nitrogenase variant has a slightly different cluster, containing two μ-S atoms. Recent crystal structures have revealed substitution of one μ-S (S2B, bridging Fe2 and Fe6), by CO in Mo-nitrogenase and an uncertain light atom in V-nitrogenase. These systems retained catalytic activity, and were able to recover the lost μ-S atom. Electron density attributed to the dissociated S is displaced by 7 Å in the crystal structure of the non-standard V-protein. The hypothesis arising from these observations is that the chemical mechanism of nitrogenase involves reversible dissociation of S2B, leaving Fe2 and Fe6 seriously under-coordinated and reactive in trapping N2 and binding reaction intermediates. Accumulated experimental evidence points to the Fe2–S2B–Fe6 domain as the centre of catalytic hydrogenation of N2. Using DFT simulations of a large model (>488 atoms) containing all relevant surrounding protein residues, I have investigated the chemical steps that could allow dissociation of S2B. The participation of H atoms is crucial, as is involvement of the nearby side chain of His195 that can function as proton donor to S2B and hydrogen-bonding supporter of displaced S2B. A significant result is that after ingress and binding of N2 at Fe2 the breaking of the Fe2–S2B bond can be strongly exergonic with negligible kinetic barrier. Subsequent extension of the Fe6–S2B bond and dissociation as H2S (or SH) is endergonic by 20–25 kcal mol−1, partly because the separating H2S is restricted by surrounding amino-acids. I present a number of reaction sequences and energy landscapes, and derive thirteen chemical principles relevant to the postulated S-dissociation mechanism. A key conclusion is that unhooking of S2BH or S2BH2 from Fe2 is favourable, likely, and propitious for subsequent H transfer to bound N2 or reaction intermediates. The space between Fe2 and Fe6 supports two bridging ligands, and another H atom on Fe6 can move without kinetic barrier to occupy the bridging position vacated by S2B.

Graphical abstract: How feasible is the reversible S-dissociation mechanism for the activation of FeMo-co, the catalytic site of nitrogenase?

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Publication details

The article was received on 14 Nov 2018, accepted on 19 Dec 2018 and first published on 04 Jan 2019


Article type: Paper
DOI: 10.1039/C8DT04531C
Citation: Dalton Trans., 2019,48, 1251-1262
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    How feasible is the reversible S-dissociation mechanism for the activation of FeMo-co, the catalytic site of nitrogenase?

    I. Dance, Dalton Trans., 2019, 48, 1251
    DOI: 10.1039/C8DT04531C

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