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Abstract

[Fe]‐hydrogenase (Hmd) catalyzes the reversible hydrogenation of methenyltetrahydromethanopterin (methenyl‐H₄MPT⁺) with H₂. Hmd contains the iron–guanylylpyridinol (FeGP) cofactor, which is sensitive to light and oxidative stress. A natural protection mechanism is reported for Hmd based on structural and biophysical data. Hmd from Methanothermobacter marburgensis (mHmd) was found in a hexameric state, where an expanded oligomerization loop is detached from the dimer core and intrudes into the active site of a neighboring dimer. An aspartic acid residue from the loop ligates to Fe^II of the FeGP cofactor and thus blocks the postulated H₂‐binding site. In solution, this enzyme is in a hexamer‐to‐dimer equilibrium. Lower enzyme concentrations, and the presence of methenyl‐H₄MPT⁺, shift the equilibrium toward the active dimer side. At higher enzyme concentrations—as present in the cell—the enzyme is predominantly in the inactive hexameric state and is thereby protected against light and oxidative stress.